This invention relates to new heterobicyclic derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
Some heterobicyclic derivatives have been known as described, for example, in EP 0 008 864 A2.
This invention relates to new heterobicyclic derivatives.
One object of this invention is to provide the new and useful pyridopyrazine derivatives and pharmaceutically acceptable salts thereof which possess a strong phosphodiesterase IV (PDE IV)-inhibitory activity and a strong inhibitory activity on the production of tumor necrosis factor (TNF).
Another object of this invention is to provide processes for preparation of the pyridopyrazine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said pyridopyrazine derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said pyridopyrazine derivatives or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases such as chronic inflammatory diseases, specific autoimmune diseases, sepsis-induced organ injury, and the like in human being and animals.
The object pyridopyrazine derivatives of the present invention are novel and can be represented by the following general formula (I): 
wherein
R1 is aryl which may have suitable substituent(s), ar(lower)alkyl which may have suitable substituent(s), halo(lower)alkyl, protected carboxy(lower)alkyl, acyl(lower)alkyl, heterocyclic group or heterocyclic(lower)alkyl which may have suitable substituent(s),
R2 is aryl which may have suitable substituent(s) or heterocyclic group, and
R3 is hydrogen, lower alkoxy or arylthio.
The object compound (I) of the present invention can be prepared by the following processes. 
wherein
R1, R2 and R3 are each as defined above,
Ra1 is halo(lower)alkyl,
Ra2 is aryl having amino or aryl having aminoaryl,
Rb2 is aryl having acylamino or aryl having acylaminoaryl,
R4 is lower alkyl,
R5 is N-protective group,
Y is halogen,
Yxe2x8ax96 is halide, and
A is lower alkylene.
The starting compound (II) of the present invention can be prepared by the following processes. 
wherein
R2, R3 and R4 are each as defined above,
R6 is heterocyclic group which may have 1 to 3 halogen,
R7 is aryl,
R8 is aryl having acylamino,
R9 is lower alkyl, and
X1, X2, X3, X4 and X5 are each a leaving group.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term xe2x80x9clowerxe2x80x9d is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
The term xe2x80x9chigherxe2x80x9d is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkyl moietyxe2x80x9d in the terms xe2x80x9car(lower)alkylxe2x80x9d, halo(lower)alkyl, xe2x80x9cprotected carboxy(lower)alkylxe2x80x9d, xe2x80x9cacyl(lower)alkylxe2x80x9d, xe2x80x9cheterocyclic(lower)alkylxe2x80x9d and xe2x80x9cheterocyclicoxycarbonyl(lower)alkylxe2x80x9d may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, and in which more preferable example may be C1-C4 alkyl.
Suitable xe2x80x9clower alkenylxe2x80x9d may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example may be C2-C4 alkenyl.
Suitable xe2x80x9clower alkynylxe2x80x9d may include ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, and the like.
Suitable xe2x80x9clower alkoxyxe2x80x9d may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable xe2x80x9clower alkylenexe2x80x9d may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which more preferable example may be C1-C4 alkylene and the most preferable one may be methylene.
Suitable xe2x80x9ccyclo(lower)alkylxe2x80x9d may include cyclopentyl, cyclohexyl and the like.
Suitable xe2x80x9ccyclo(lower)alkenylxe2x80x9d may include cyclohexenyl, cyclohexadienyl and the like.
Suitable xe2x80x9carylxe2x80x9d and xe2x80x9caryl moietyxe2x80x9d in the terms xe2x80x9car(lower)alkylxe2x80x9d, xe2x80x9carylthioxe2x80x9d, xe2x80x9caminoarylxe2x80x9d and xe2x80x9cacylaminoarylxe2x80x9d may include phenyl, naphthyl and the like.
Suitable xe2x80x9chalogenxe2x80x9d and xe2x80x9chalogen moietyxe2x80x9d in the term xe2x80x9chalo(lower)alkylxe2x80x9d may include fluorine, bromine, chlorine and iodine.
Suitable xe2x80x9cleaving groupxe2x80x9d may include acid residue, lower alkoxy as exemplified above, and the like.
Suitable xe2x80x9cacid residuexe2x80x9d may include halogen as exemplified above, acyloxy and the like.
Suitable xe2x80x9chalidexe2x80x9d may include fluoride, bromide, chloride and the like.
Suitable xe2x80x9cprotected carboxyxe2x80x9d and xe2x80x9cprotected carboxy moietyxe2x80x9d in the term xe2x80x9cprotected carboxy(lower)alkylxe2x80x9d may include esterified carboxy and the like. And suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthio(lower)alkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropoxythiomethyl ester, etc.); mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-(or 2-)-[methoxycarbonyloxy]ethyl ester, 1-(or 2-)-[ethoxycarbonyloxy]ethyl ester, 1-(or 2-)-[propoxycarbonyloxy]ethyl ester, 1-(or 2-)-[isopropoxycarbonyloxy]ethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.); phthalidylidene(lower)alkyl ester; (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; mono(or di or tri)alkyl(lower)alkyl ester, for example, mono(or di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower)alkylsilyl ester; lower alkylthioester (e.g. methylthioester, ethylthioester, etc.) and the like.
Suitable xe2x80x9chydroxy protective groupxe2x80x9d in the term xe2x80x9cprotected hydroxyxe2x80x9d may include acyl, mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
Suitable xe2x80x9cN-protective groupxe2x80x9d may include acyl or a conventional protecting group such as mono (or di or tri)aryl(lower)alkyl, for example, mono(or di or tri)phenyl(lower)alkyl (e.g., benzyl, trityl, etc.) or the like.
Suitable xe2x80x9cprotected aminoxe2x80x9d may include acylamino or an amino group substituted by a conventional protecting group such as mono (or di or tri)aryl(lower)alkyl, for example, mono(or di or tri)phenyl(lower)alkyl (e.g., benzyl, trityl, etc.) or the like.
Suitable xe2x80x9cacylxe2x80x9d and xe2x80x9cacyl moietyxe2x80x9d in the terms xe2x80x9cacylaminoxe2x80x9d, xe2x80x9cacyloxyxe2x80x9d and xe2x80x9cacyl(lower)alkylxe2x80x9d may include carbamoyl, thiocarbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows:
Carbamoyl; Thiocarbamoyl; Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); lower or higher alkenoyl (e.g., acryloyl, 2-(or 3-)butenoyl, 2-(or 3- or 4-)pentenoyl, 2-(or 3- or 4- or 5-)hexenoyl, etc.); lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); lower alkadienoyl (e.g., heptadienoyl, hexadienoyl, etc.); cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); cyclo(lower)alkylidene(lower)alkanoyl (e.g., cycloheptylideneacetyl, cycloheptylidenepropanoyl, cyclohexylideneacetyl, cyclohexylidenepropanoyl, etc.); cyclo(lower)alkyloxycarbonyl (e.g., cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.); lower alkylglyoxyloyl (e.g., methylglyoxyloyl, ethylglyoxyloyl, propylglyoxyloyl, etc.); lower alkoxyglyoxyloyl (e.g., methoxyglyoxyloyl, ethoxyglyoxyloyl, propoxyglyoxyloyl, etc.); or the like;
Aromatic acyl such as
aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); ar(lower)alkylsulfonyl [e.g., phenyl(lower)alkylsulfonyl (e.g., benzylsulfonyl, phenylethylsulfonyl, etc.), naphthyl(lower)alkylsulfonyl (e.g., naphthylmethylsulfonyl, naphthylethylsulfonyl, etc.), etc.]; or the like;
Heterocyclic acyl such as
heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; heterocyclicoxycarbonyl; or the like; in which suitable xe2x80x9cheterocyclic moietyxe2x80x9d in the terms xe2x80x9cheterocycliccarbonylxe2x80x9d, xe2x80x9cheterocyclic(lower)alkanoylxe2x80x9d, heterocyclic(lower)alkenoylxe2x80x9d, heterocyclicoxycarbonyl and xe2x80x9cheterocyclicglyoxyloylxe2x80x9d as mentioned above means, in more detail, saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, especially preferable heterocyclic group may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, indazolyl, benzotriazolyl, benzopyrimidinyl (e.g., benzo[b]pyrimidinyl, etc.), etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzodioxolyl (e.g. methylenedioxyphenyl, etc.), benzofuryl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl (e.g., benzo[b]thienyl, etc.), benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.
The acyl moiety as stated above may have one to ten, same or different, suitable substituent(s) such as lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkylthio wherein lower alkyl moiety is as exemplified above, cyclo(lower)alkyl as exemplified above, cyclo(lower)alkenyl as exemplified above, cyclo(lower)alkyloxy wherein cyclo(lower)alkyl moiety is as exemplified above, halogen as exemplified above, amino, protected amino as exemplified above, hydroxy, protected hydroxy as exemplified above, cyano, nitro, carboxy, protected carboxy as exemplified above, sulfo, sulfamoyl, imino, oxo, amino(lower)alkyl wherein lower alkyl moiety is as exemplified above, carbamoyloxy, mono(or di or tri)halo(lower)alkyl wherein halogen moiety and lower alkyl moiety are each as exemplified above, hydroxy(lower)alkyl wherein lower alkyl moiety is as exemplified above, heterocyclic group as exemplified above, heterocyclicoxy wherein heterocyclic moiety is as exemplified above, heterocyclicamino which may have nitro wherein heterocyclic moiety is as exemplified above, aryl which may have suitable substituent(s) wherein aryl moiety is as exemplified above, arylsulfonyl wherein aryl moiety is as exemplified above, ar(lower)alkyl wherein aryl moiety and lower alkyl moiety are each as exemplified above, protected carboxy(lower)alkenyl wherein protected carboxy moiety and lower alkenyl moiety are each as exemplified above, acyl as exemplified above, acylamino wherein acyl moiety is as exemplified above, or the like.
Suitable xe2x80x9cheterocyclic groupxe2x80x9d and xe2x80x9cheterocyclic moietyxe2x80x9d in the terms xe2x80x9cheterocyclic(lower)alkylxe2x80x9d and xe2x80x9cheterocyclicoxycarbonyl(lower)alkylxe2x80x9d can be referred to the ones as mentioned above.
Suitable xe2x80x9csubstituentxe2x80x9d in the term xe2x80x9car(lower)alkyl which may have suitable substituent(s)xe2x80x9d may include lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkenyl as exemplified above, lower alkynyl as exemplified above, mono(or di or tri)halo(lower)alkyl wherein halogen moiety and lower alkyl moiety are each as exemplified above, cyclo(lower)alkyl as exemplified above, cyclo(lower)alkenyl as exemplified above, halogen as exemplified above, carboxy, protected carboxy as exemplified above, hydroxy, protected hydroxy as exemplified above, aryl as exemplified above, ar(lower)alkyl wherein aryl moiety and lower alkyl moiety are each as exemplified above, carboxy(lower)alkyl wherein lower alkyl moiety is as exemplified above, protected carboxy(lower)alkyl wherein protected carboxy moiety and lower alkyl moiety are each as exemplified above, nitro, amino, protected amino as exemplified above, di(lower)alkylamino wherein lower alkyl moiety is as exemplified above, amino(lower)alkyl wherein lower alkyl moiety is as exemplified above, protected amino(lower)alkyl wherein protected amino moiety and lower alkyl moiety are each as exemplified above, hydroxy(lower)alkyl wherein lower alkyl moiety is as exemplified above, protected hydroxy(lower)alkyl wherein protected hydroxy moiety and lower alkyl moiety are each as exemplified above, acyl as exemplified above, cyano, sulfo, sulfamoyl, carbamoyloxy, mercapto, lower alkylthio wherein lower alkyl moiety is as exemplified above, imino, and the like.
Suitable xe2x80x9csubstituentxe2x80x9d in the term xe2x80x9caryl which may have suitable substituent(s)xe2x80x9d may include lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkenyl as exemplified above, lower alkynyl as exemplified above, mono(or di or tri)halo(lower)alkyl wherein halogen moiety and lower alkyl moiety are each as exemplified above, cyclo(lower)alkyl as exemplified above, cyclo(lower)alkenyl as exemplified above, halogen as exemplified above, cyclo(lower)alkyloxy wherein cyclo(lower)alkyl moiety is as exemplified above, carboxy, protected carboxy as exemplified above, hydroxy, protected hydroxy as exemplified above, aryl as exemplified above, ar(lower)alkyl wherein aryl moiety and lower alkyl moiety are each as exemplified above, carboxy(lower)alkyl wherein lower alkyl moiety as exemplified above, protected carboxy(lower)alkyl wherein protected carboxy moiety and lower alkyl moiety are each as exemplified above, nitro, amino, protected amino as exemplified above, acylamino wherein acyl moiety is as exemplified above, di(lower)alkylamino wherein lower alkyl moiety is as exemplified above, amino(lower)alkyl wherein lower alkyl moiety is as exemplified above, protected amino(lower)alkyl wherein protected amino moiety and lower alkyl moiety are each as exemplified above, hydroxy(lower)alkyl wherein lower alkyl moiety is as exemplified above, protected hydroxy(lower)alkyl wherein protected hydroxy moiety and lower alkyl moiety are each as exemplified above, acyl as exemplified above, cyano, sulfo, sulfamoyl, carbamoyloxy, mercapto, lower alkylthio wherein lower alkyl moiety is as exemplified above, lower alkylamino wherein lower alkyl moiety is as exemplified above, N-acyl-N-lower alkylamino wherein acyl moiety and lower alkyl moiety are each as exemplified above, acyl(lower)alkyl wherein acyl moiety and lower alkyl moiety are each as exemplified above, ar(lower)alkenyl which may have 1 to 3 halogen wherein aryl moiety, lower alkenyl moiety and halogen moiety are each as exemplified above, acyl(lower)alkenyl wherein acyl moiety, and lower alkenyl moiety are each as exemplified above, protected carboxy(lower)alkenyl wherein protected carboxy moiety and lower alkenyl moiety are each as exemplified above, cyano(lower)alkenyl wherein lower alkenyl moiety is as exemplified above, heterocyclicoxy which may have 1 to 3 aryl wherein heterocyclic moiety and aryl moiety are each as exemplified above, imino, [heterocyclicamino which may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl and aryl] wherein heterocyclic moiety, lower alkyl moiety and aryl moiety are each as exemplified above; [aryl which may have 1 to 3 substituent(s) selected from the group consisting of carboxy(lower)alkenyl, protected carboxy(lower)alkenyl, aryl, lower alkoxy, cyclo(lower)alkyloxy, halogen, carboxy, protected carboxy, amino, acylamino, diacylamino and acyl] wherein aryl moiety, lower alkenyl moiety, protected carboxy moiety, lower alkoxy moiety, cyclo(lower)alkyl moiety, halogen moiety and acyl moiety are each as exemplified above; heterocyclic(lower)alkenyl which may have 1 to 3 halogen wherein heterocyclic moiety, lower alkenyl moiety and halogen moiety are each as exemplified above; [heterocyclic group which may have 1 to 3 substituent(s) selected from the group consisting of halogen, cyano, carboxy, protected carboxy, oxo, acyl, amino, protected amino and heterocyclic group] wherein heterocyclic moiety, halogen moiety, protected carboxy moiety, acyl moiety and protected amino moiety are each as exemplified above; and the like.
Suitable xe2x80x9csubstituentxe2x80x9d in the term xe2x80x9cheterocyclic(lower)alkyl which may have suitable substituent(s)xe2x80x9d may include lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkenyl as exemplified above, lower alkynyl as exemplified above, mono(or di or tri)halo(lower)alkyl wherein halogen moiety and lower alkyl moiety are each as exemplified above, cyclo(lower)alkyl as exemplified above, cyclo(lower)alkenyl as exemplified above, halogen as exemplified above, carboxy, protected carboxy as exemplified above, hydroxy, protected hydroxy as exemplified above, aryl as exemplified above, ar(lower)alkyl wherein aryl moiety and lower alkyl moiety are each as exemplified above, carboxy(lower)alkyl wherein lower alkyl moiety as exemplified above, protected carboxy(lower)alkyl wherein protected carboxy moiety and lower alkyl moiety are each as exemplified above, nitro, amino, protected amino as exemplified above, di(lower)alkylamino wherein lower alkyl moiety is as exemplified above, amino(lower)alkyl wherein lower alkyl moiety is as exemplified above, protected amino(lower)alkyl wherein protected amino moiety and lower alkyl moiety are each as exemplified above, hydroxy(lower)alkyl wherein lower alkyl moiety is as exemplified above, protected hydroxy(lower)alkyl wherein protected hydroxy moiety and lower alkyl moiety are each as exemplified above, acyl as exemplified above, cyano, sulfo, sulfamoyl, carbamoyloxy, mercapto, lower alkylthio wherein lower alkyl moiety is as exemplified above, imino, and the like.
The processes for preparing the object and the starting compounds are explained in detail in the following.
Process (1)
The compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
Process (2)
The compound (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or its reactive derivative at the amino group or a salt thereof to acylation reaction.
Suitable acylating agent to be used in the present acylation reaction may include the compound of the formula:
R10xe2x80x94OHxe2x80x83xe2x80x83(VII)
(wherein R10 is acyl) or its reactive derivative or a salt thereof.
Suitable reactive derivative at the amino group of the compound (Ia) may include Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (Ia) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (Ia) with a silyl compound such as N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (Ia) with phosphorus trichloride or phosgene, and the like.
Suitable reactive derivative of the compound (VII) may include an acid halide, an acid anhydride, an activated ester, isocyanate, and the like. The suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfuric acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl 
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.); substituted or unsubstituted aryl isocyanate; substituted or unsubstituted aryl isothiocyanate, and the like. These reactive derivatives can optionally be selected from them accordingly to the kind of the compound (VII) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
When the compound (VII) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,N-carbonyl-bis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride; thionyl chloride; oxalyl chloride; triphenylphosphite; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower) alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
Process (3)
The compound (Ia) or a salt thereof can be prepared by subjecting the compound (Ib) or a salt thereof to deacylation reaction.
Suitable method of this deacylation reaction may include conventional one such as hydrolysis, reduction and the like.
(i) For Hydrolysis
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, or the like.
Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
The elimination using Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid, trifluoroacetic acid, etc.], or the like is preferably carried out in the presence of cation trapping agents [e.g., anisole, phenol, etc.].
The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl, alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
(ii) For Reduction
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.), or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, Ullman iron, etc.), and the like.
The reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
Process (4)
The compound (Ic) or a salt thereof can be prepared by subjecting the compound (XI) or a salt thereof to halogenation reaction.
This halogenation is usually carried out by using a conventional halogenating agent such as halogen (e.g., chlorine, bromine, etc.), phosphorus trihalide (e.g., phosphorus tribromide, phosphorus trichloride, etc.), phosphorus pentahalide (e.g., phosphorus pentachloride, phosphorus pentabromide, etc.), phosphorus oxychloride (e.g., phosphoryl trichloride, phosphoryl monochloride, etc.), thionyl halide (e.g., thionyl chloride, thionyl bromide, etc.), oxalyl halide (e.g., oxalyl chloride, oxalyl bromide, etc.), N-halosuccinimide (e.g. N-bromosuccinimide, N-chlorosuccinimide, etc.) and the like.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), benzene, dioxane, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Process (5)-{circle around (1)}
The compound (IX) or a salt thereof can be prepared by reacting the compound (Id) or a salt thereof with the compound (VIII) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The reaction is usually carried out in the presence of an acid including Lewis acid.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g. zinc chloride, zinc bromide, etc.), etc.] and the like.
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydrogencarbonate (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), tri(lower)alkylamine (e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkali metal (lower)alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.
When the base, the acid and/or the starting compound are in liquid, they can be used also as a solvent.
Process (5)-{circle around (2)}
The compound (Ie) or a salt thereof can be prepared by subjecting the compound (IX) or a salt thereof to elimination reaction of N-protective group.
This reaction can be carried out in a similar manner to that of the aforementioned Process (3), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3).
Process (A)-{circle around (1)}
The compound (VI) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
When the starting compound is in liquid, it can be also used as a solvent.
Process (A)-{circle around (2)}
The compound (II) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to reduction reaction.
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, etc.), copper catalysts (e.g., reduced copper, Raney copper, Ullman copper, etc.) and the like.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), tetrahydrofuran, dioxane, N,N-dimethylformamide, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Process (B)
The compound (XI) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (X) or a salt thereof.
This reaction can be carried out in a similar manner to that of the aforementioned Process (1), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (1).
Process (C)
The compound (V) or a salt thereof can be prepared by subjecting the compound (XII) or a salt thereof to reduction reaction.
This reaction can be carried out in a similar manner to that of the aforementioned Process (A)-{circle around (2+L )}, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (A)-{circle around (2)}.
The present invention includes, within the scope of the invention, the case that a maleimidophenyl group is transformed into a succinimidophenyl group during the reaction.
Process (D)
The compound (VIa) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (XIV) or a salt thereof.
The reaction can be carried out in the manner disclosed in Preparation 51 or similar manners thereto.
Process (E)
The compound (XIIa) or a salt thereof can be prepared by reacting the compound (XV) or a salt thereof with the compound (XVI) or a salt thereof.
The reaction can be carried out in the manner disclosed in Preparation 41 or similar manners thereto.
Process (F)
The compound (XIIb) or a salt thereof can be prepared by reacting the compound (XVII) with the compound (XVIII) or a salt thereof.
The reaction can be carried out in the manner disclosed in Preparation 38 or similar manners thereto.
Process (G)
The compound (Va) or a salt thereof can be prepared by reacting the compound (XIX) or a salt thereof with the compound (XX) or a salt thereof.
The reaction can be carried out in the manner disclosed in Preparation 4, 61, 62 or 63, or similar manners thereto.
Process (H)-{circle around (1)}
The compound (XXII) or a salt thereof can be prepared by reacting the compound (XIIc) or a salt thereof with the compound (XXI).
The reaction can be carried out in the manner disclosed in Preparation 77 or similar manners thereto.
Process (H)-{circle around (2)}
The compound (XXIII) or a salt thereof can be prepared by subjecting the compound (XXII) or a salt thereof to dehydration reaction.
The reaction can be carried out in the manner disclosed in Preparation 78 or similar manners thereto.
Process (I)
The compound (XIIb) or a salt thereof can be prepared by reacting the compound (XXIV) or a salt thereof with the compound (XXV) or a salt thereof.
The reaction can be carried out in the manner disclosed in Preparation 42 or similar manners thereto.
Suitable salts of the object and the starting compounds in Processes (1)xcx9c(5) and (A)xcx9c(I) can be referred to the ones as exemplified for the compound (I).
The new pyridopyrazine derivatives (I) and pharmaceutically acceptable salts thereof hardly possess a strong inhibitory activity against phosphodiesterase III (PDE III), but possess a strong inhibitory activity against phosphodiesterase IV (PDE IV) and a strong inhibitory activity on the tumor necrosis factor (TNF).
That is, the pyridopyrazine derivatives (I) and pharmaceutically acceptable salts thereof are selective inhibitors of phosphodiesterase IV (PDE IV) and inhibitors on the production of tumor necrosis factor (TNF).
Accordingly, the new pyridopyrazine derivatives (I) and a pharmaceutically acceptable salt thereof can be used for prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases such as chronic inflammatory diseases (e.g., rheumatoid arthritis, osteoarthritis, emphysema, chronic bronchiolitis, etc.), osteoporosis, rejection by transplantation, asthma, eosinophilia, cystic fibrosis, hepatitis, pancreatitis, nephritis, endotoxin shock, specific autoimmune diseases [e.g., ankylosing spondylitis, autoimmune hematological disorders (e.g., hemolyticodo anaemia, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopenia, etc.), systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulamotosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, atopic dermatitis, psoriasis, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis, Crohn""s disease, etc.), endocrine ophthalmopathy, Grave""s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), Reiter""s syndrome, non infection uveitis, autoimmune keratitis (e.g., keratoconjunctivitis sicca, vernal keratoconjunctivitis, etc.), interstitial lung fibrosis, psoriatic arthritis, etc.], cancer cachexia, AIDS cachexia, thrombosis, and the like.
In order to show the utilities of the pyridopyrazine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the pyridopyrazine derivatives (I) are illustrated in the following.
(a) Inhibition of U937 Phosphodiesterase IV (PDE IV)
1. Test Method
Harvested U937 was freezed in xe2x88x9280xc2x0 C. and throwed to destroy the cell body. The pellet of destroyed cell was washed by Phosphate-buffered saline (PBS).
The washed cell pellet was homogenized with Dounce homogenizer (20 strokes) in homogenizing buffer (0.5% deoxycholate [DOC], 5 mM 2-mercaptoethanol, 1 xcexcM leupeptin, 100 xcexcM PMSF, 20 xcexcM p-tosyl-L-lysine-chloromethyl ketone [TLCK] in PBS). The homogenate was centrifuged at 100,000 gxc3x9790 minutes (4xc2x0 C.) and the supernatant containing PDE IV activity was dialyzed against dialysis buffer, which was the same component as homogenizing buffer without DOC. The dialyzed supernatant of homogenate was stored in freezer (xe2x88x9280xc2x0 C.) as PDE IV enzyme preparation.
Enzyme preparation was diluted in assay buffer (10 mM Tris-HCl, 5 mM MgCl, 1 mM 2-Mercaptoethanol [pH 8.0]). In advance the rate of dilution was choosen every new lot of homogenizing preparation. For blank, a part of the enzyme preparation was boiled for 10 minutes.
Test compounds were dissolved in dimethylsulfoxide (DMSO) at a concentration of 4xc3x9710(xe2x88x922)[M] (final conc. 1xc3x9710(xe2x88x925)M), then serial dilutions were made in DMSO to achieve desired concentrations. The diluted compounds of each concentration were further diluted 1:500 in assay buffer (0.2% DMSO). Final DMSO concentration in assay tube was 0.025%.
In duplicate, the followings were added to a glass tube, in order, at 0xc2x0 C. (all concentrations are given as final concentrations in assay tube).
50 xcexcl compound or assay buffer for control or blank
50 xcexcl 8xc3x9710(xe2x88x925)[M] CI-930 (final 10 xcexcM): (CI-930 is PDE III inhibitor)
200 xcexcl enzyme preparation or boiled enzyme preparation for blank.
The reaction tube was preincubated in a water bath (30xc2x0 C.) for 5 minutes, then 100 xcexcl [3H]-cAMP (37.0 MBq/ml [3H]-cAMP: 4 xcexcM cold cAMP=1:800) was added thereto. After 15 minutes, 2.5 units/ml alkaline phosphatase was added to the reaction mixture and the reaction was continued for 15 minutes. Dowex 1xc3x978 gel was added to the reaction mixture and was vortexed well. The mixture was centrifuged at 1000 rpmxc3x975 minutes, and then 500 xcexcl of the supernatant was added to 10 ml scintillation fluid in appropriate vial, vortexed, and counted for [3H].
The inhibitory activity was calculated according to the following equation:       %    ⁢          xe2x80x83        ⁢    Inhibition    =      100    -                                                                                        avg                  .                                      xe2x80x83                                    ⁢                                      cpm                    ⁢                                          xe2x80x83                                        [                                          test                      ⁢                                              xe2x80x83                                            ⁢                      compound                                        ]                                                  -                                                                                        avg                .                                  xe2x80x83                                ⁢                                  cpm                  ⁢                                      xe2x80x83                                    [                                      blank                    ⁢                                                                  xe2x80x83                                            ⁢                                              xe2x80x83                                                              (                                          boiled                      ⁢                                              xe2x80x83                                            ⁢                      enzyme                                        )                                    ]                                                                                                                                          avg                  .                                      xe2x80x83                                    ⁢                                      cpm                    ⁢                                          xe2x80x83                                        [                                          control                      ⁢                                              xe2x80x83                                            ⁢                                              (                                                  no                          ⁢                                                      xe2x80x83                                                    ⁢                          compound                                                )                                                              ]                                                  -                                                                                        avg                .                                  xe2x80x83                                ⁢                                  cpm                  ⁢                                      xe2x80x83                                    [                                      blank                    ⁢                                          xe2x80x83                                        ⁢                                          (                                              boiled                        ⁢                                                  xe2x80x83                                                ⁢                        enzyme                                            )                                                        ]                                                                        xc3x97      100      
2. Test Compound
(a) 4-[3-[3-(1-Naphthyl)ureido]phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
3. Test Result
(b) Inhibition on TNF-xcex1 production in human mononuclear cells
1. Test Method
Blood was drawn from healthy volunteers with heparin. The mononuclear cell (MNC) fraction was obtained by gradient centrifugation (1800 rpm, 15 minutes), diluted with the same volume of RPMI-1640 culture medium, over Ficoll-Paque (Pharmacia LKB Biotechnology). MNC were washed twice with RPMI-1640. Then, MNC were resuspended in RPMI-1640 culture medium supplemented with 2 mM L-glutamine and 1% fetal bovine serum. MNC were incubated at 37xc2x0 C. for 16 hours in 96-well micro culture plate at a concentration of 3xc3x9710xe2x88x925 cells/well with or without 1 xcexcg/ml lipopolysaccharide (LPS)(from E. coli) and various amounts of test compound. At the end of incubation, the supernatant was obtained and its TNF-xcex1 active was measured by enzyme-linked immunosorbent assay (ELISA). ELISA was performed with TNF-xcex1 ELISA kit (Otsuka Pharmaceutical Co., Ltd.).
2. Test Compound
(a) 4-[3-[3-(1-Naphthyl)ureido]phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
3. Test Result
For therapeutic administration, the object compounds (I) of the present invention and pharmaceutically acceptable salts thereof are used in a form of the conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution, suspension or emulsion for injection, ingestion, eye drops, etc. If needed, there may be included in the above preparation auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
The effective ingredient may usually be administered with a unit dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight and conditions of the patient or the administering method.
Preferred embodiments of the object compound (I) are as follows.
R1 is phenyl which may have 1 to 3 (more preferably one or two; most preferably one) suitable substituent(s) (more preferably nitro); phenyl(lower)alkyl which may have 1 to 3 (more preferably one or two;
most preferably one) suitable substituent(s) [more preferably substituent selected from the group consisting of nitro, amino, protected amino (more preferably acylamino), hydroxy and protected hydroxy (more preferably acyloxy; most preferably lower alkanoyloxy)]; halo(lower)alkyl; protected carboxy(lower)alkyl (more preferably esterified carboxy(lower)alkyl; most preferably lower alkoxycarbonyl(lower)alkyl); carbamoyl(lower)alkyl which may have one or two suitable substituent(s) [more preferably substituent selected from the group consisting of lower alkyl and heterocyclic group (more preferably pyrrolidinyl)]; heterocyclicoxycarbonyl(lower)alkyl (more preferably pyrrolidinyloxycarbonyl(lower)alkyl) which may have 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably oxo); heterocycliccarbonyl(lower)alkyl (more preferably pyrrolidinylcarbonyl(lower)alkyl or piperazinylcarbonyl(lower)alkyl) which may have 1 to 3 (more preferably one or two; most preferably one) substituent(s) selected from the group consisting of protected carboxy (more preferably esterified carboxy; most preferably lower alkoxycarbonyl) and lower alkyl; indolyl; or indolyl(lower)alkyl, pyridyl(lower)alkyl, imidazolyl(lower)alkyl, morpholinyl(lower)alkyl or triazolyl(lower)alkyl, each of which may have 1 to 3 (more preferably one or two; most preferably one) suitable substituent(s) [more preferably substituent selected from the group consisting of lower alkyl, N-oxide and aryl (more preferably phenyl)];
R2 is phenyl or naphthyl, each of which may have 1 to 3 (more preferably one or two) suitable substituent(s) {more preferably substituent selected from the group consisting of lower alkyl; halogen; mono(or di or tri)halo(lower)alkyl (more preferably trihalo(lower)alkyl); hydroxy; protected hydroxy (more preferably acyloxy; most preferably lower alkanoyloxy); carboxy; protected carboxy (more preferably esterified carboxy; most preferably lower alkoxycarbonyl or phenyl(lower)alkoxycarbonyl); carboxy(lower)alkyl; protected carboxy(lower)alkyl (more preferably esterified carboxy(lower)alkyl; most preferably lower alkoxycarbonyl(lower)alkyl); lower alkoxy; cyano; nitro; amino; acylamino [more preferably lower alkanoylamino; aryloxycarbonylamino (more preferably phenyl(lower)alkoxycarbonylamino); lower alkoxycarbonylamino; lower alkoxyglyoxyloyl; cyclo(lower)alkylcarbonylamino; cyclo(lower)alkyloxycarbonylamino; cyclo(lower)alkylidene(lower)alkanoylamino; aroylamino (more preferably benzoylamino or naphthoylamino) which may have 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of lower alkyl, halogen, lower alkoxy, carboxy, protected carboxy (more preferably esterified carboxy; most preferably lower alkoxycarbonyl), nitro, hydroxy, protected hydroxy (more preferably acyloxy; most preferably lower alkanoyloxy), mono(or di or tri)halo(lower)alkyl (more preferably trihalo(lower)alkyl), cyclo(lower)alkyloxy, aryl (more preferably phenyl), carboxy(lower)alkenyl, protected carboxy(lower)alkenyl (more preferably esterified carboxy(lower)alkenyl; most preferably lower alkoxycarbonyl(lower)alkenyl), amino, protected amino (more preferably aroylamino; most preferably benzoylamino), heterocyclicoxy (more preferably pyrimidinyloxy), and heterocyclicamino (more preferably pyridylamino) which may have nitro; arylsulfonylamino (more preferably phenylsulfonylamino) which may have one or two halogen; ar(lower)alkylsulfonylamino (more preferably phenyl(lower)alkylsulfonylamino); cyclo(lower)alkylcarbonylamino; [mono(or di)ar(lower)alkanoyl]amino (more preferably [mono (or di)phenyl(lower) alkanoyl]amino or [naphthyl(lower)alkanoyl]amino); lower alkadienoylamino; heterocycliccarbonylamino (more preferably furylcarbonylamino, pyridylcarbonylamino, thienylcarbonylamino, indolylcarbonylamino, indolinylcarbonylamino, quinolylcarbonylamino, tetrahydroquinolylcarbonylamino, benzofurylcarbonylamino, benzothienylcarbonylamino, methylenedioxybenzoylamino or morpholinylcarbonylamino) which may have 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of lower alkyl and halogen; ar(lower)alkenoylamino (more preferably phenyl(lower)alkenoylamino) which may have 1 to 3 (more preferably one or two; most preferably one) substituent(s) selected from the group consisting of lower alkyl, halogen, carboxy, protected carboxy (more preferably esterified carboxy; most preferably lower alkoxycarbonyl) and nitro; heterocyclic(lower)alkenoylamino (more preferably pyridyl(lower)alkenoylamino); carbamoylamino which may have one or two substituent(s) selected from the group consisting of lower alkyl; aryl (more preferably phenyl or naphthyl) which may have 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of nitro, amino, protected amino (more preferably acylamino), lower alkoxy, lower alkylthio, lower alkyl, aryl (more preferably phenyl), carboxy, protected carboxy (more preferably esterified carboxy; most preferably lower alkoxycarbonyl), di(lower)alkylamino, mono(or di or tri)halo(lower)alkyl (more preferably trihalo(lower)alkyl) and halogen; arylsulfonyl (more preferably phenylsulfonyl); ar(lower)alkyl (more preferably phenyl(lower)alkyl); cyclo(lower)alkyl; and heterocyclic group (more preferably thiazolyl, pyridyl, quinolyl or morpholinyl); or thiocarbamoylamino which may have one or two (more preferably one) substituent(s) selected from the group consisting of aryl (more preferably phenyl or naphthyl) and acyl (more preferably aroyl; most preferably benzoyl)]; lower alkylamino; N-acyl-N-lower alkylamino [more preferably N-lower alkanoyl-N-lower alkylamino, N-aroyl-N-lower alkylamino (more preferably N-benzoyl-N-lower alkylamino), N-arylcarbamoyl-N-lower alkylamino (more preferably N-phenylcarbamoyl-N-lower alkylamino) or N-protected carboxyar(lower)alkenoyl-N-lower alkylamino (more preferably N-[esterified carboxyphenyl](lower)alkenoyl-N-lower alkylamino; most preferably N-[lower alkoxycarbonylphenyl](lower)alkenoyl-N-lower alkylamino)]; heterocyclicamino (more preferably thiazolylamino or pyrimidinylamino) which may have 1 to 3 (more preferably one or two; most preferably one) substituent(s) selected from the group consisting of lower alkyl and aryl (more preferably phenyl); acyl [more preferably lower alkanoyl, carbamoyl which may have one or two substituent(s) selected from the group consisting of lower alkyl and aryl (more preferably phenyl) which may have one or two halogen, aroyl (more preferably benzoyl) which may have lower alkoxy or heterocycliccarbonyl (more preferably morpholinylcarbonyl or indolizinylcarbonyl)]; acyl(lower)alkyl [more preferably carbamoyl(lower)alkyl which may have one or two (more preferably one) aryl (more preferably phenyl or naphthyl)]; aryl (more preferably phenyl or naphthyl) which may have 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of carboxy(lower)alkenyl, protected carboxy(lower)alkenyl (more preferably esterified carboxy(lower)alkenyl; most preferably lower alkoxycarbonyl(lower)alkenyl), aryl (more preferably phenyl), lower alkoxy, cyclo(lower)alkyloxy, halogen, carboxy, protected carboxy (more preferably esterified carboxy; most preferably lower alkoxycarbonyl), amino, acylamino [more preferably lower alkanoylamino, aroylamino (more preferably benzoylamino) which may have protected carboxy (more preferably esterified carboxy) or carboxy, lower alkylsulfonylamino, mono(or di or tri)halo(lower)alkanoylamino (more preferably trihalo(lower)alkanoylamino), lower alkoxycarbonylamino, aryloxycarbonylamino (more preferably phenoxycarbonylamino), carboxy(lower)alkanoylamino, protected carboxy(lower)alkanoylamino (more preferably esterified carboxy(lower)alkanoylamino; most preferably lower alkoxycarbonyl(lower)alkanoylamino), carboxy(lower)alkenoylamino, protected carboxy(lower)alkenoylamino (more preferably esterified carboxy(lower)alkenoylamino; most preferably lower alkoxycarbonyl(lower)alkenoylamino), cyclo(lower)alkylcarbonylamino, lower alkylglyoxyloylamino, arylsulfonylamino (more preferably phenylsulfonylamino) which may have one or two halogen, ar(lower)alkenoylamino (more preferably phenyl(lower)alkenoylamino) which may have protected carboxy (more preferably esterified carboxy) or carboxy, heterocyclic(lower)alkenoylamino (more preferably pyridyl(lower)alkenoylamino), heterocycliccarbonylamino (more preferably quinoxalinylcarbonylamino or benzothienylcarbonylamino), carbamoylamino which may have one or two substituent(s) selected from the group consisting of lower alkyl and aryl (more preferably phenyl)], diacylamino (more preferably bis(lower alkylsulfonyl)amino) and acyl (more preferably carbamoyl which may have one or two substituent(s) selected from the group consisting of lower alkyl and aryl (more preferably phenyl or naphthyl); ar(lower)alkyl (more preferably phenyl(lower)alkyl or naphthyl(lower)alkyl); ar(lower)alkenyl (more preferably phenyl(lower)alkenyl or naphthyl(lower)alkenyl) which may have 1 to 3 (more preferably one or two) halogen; acyl(lower)alkenyl (more preferably aroyl(lower)alkenyl; most preferably benzoyl(lower)alkenyl); protected carboxy(lower)alkenyl (more preferably esterified carboxy(lower)alkenyl; most preferably lower alkoxycarbonyl(lower)alkenyl); cyano(lower)alkenyl; heterocyclic(lower)alkenyl (more preferably pyridyl(lower)alkenyl which may have 1 to 3 (more preferably one or two; most preferably one) halogen, pyrimidinyl(lower)alkenyl or quinolyl(lower)alkenyl); heterocyclic group (more preferably pyridyl, thienyl, pyrrolyl, pyrrolidinyl, indolyl, quinolyl, isoquinolyl, imidazolyl, thiazolyl, benzothiazolyl or triazolyl) which may have 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of halogen, cyano, carboxy, protected carboxy (more preferably esterified carboxy; most preferably lower alkoxycarbonyl), oxo, acyl (more preferably lower alkanoyl), amino, protected amino (more preferably acylamino) and heterocyclic group (more preferably pyridyl); and heterocyclicoxy (more preferably pyrimidinyloxy) which may have 1 to 3 (more preferably one or two; most preferably one) aryl (more preferably phenyl)}, or pyridyl,
R3 is hydrogen, lower alkoxy or arylthio (more preferably phenylthio).
More preferred embodiments of the object compound (I) are as follows.
R1 is phenyl, nitrophenyl, phenyl(lower)alkyl, nitrophenyl(lower)alkyl, aminophenyl(lower)alkyl, hydroxyphenyl(lower)alkyl, lower alkanoyloxyphenyl(lower)alkyl, halo(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, [pyrrolidinylcarbamoyl](lower)alkyl, [N,N-di(lower)alkylcarbamoyl](lower)alkyl, pyrrolidinylcarbonyl(lower)alkyl, [dioxopyrrolidinyloxycarbonyl](lower)alkyl, [lower alkoxycarbonylpyrrolidinylcarbonyl](lower)alkyl, [lower alkylpiperazinylcarbonyl](lower)alkyl, indolyl, indolyl(lower)alkyl, pyridyl(lower)alkyl which may have N-oxide, imidazolyl(lower)alkyl which may have lower alkyl or phenyl, or morpholinyl(lower)alkyl,
R2 is phenyl, lower alkylphenyl, halophenyl, trihalo(lower)alkylphenyl, hydroxyphenyl, lower alkanoyloxyphenyl, carboxyphenyl, lower alkoxycarbonylphenyl, [phenyl(lower)alkoxycarbonyl]phenyl, [carboxy(lower)alkyl]phenyl, [lower alkoxycarbonyl(lower)alkyl]phenyl, lower alkoxyphenyl, cyanophenyl, nitrophenyl, aminophenyl, [lower alkanoylamino]phenyl, [phenoxycarbonylamino]phenyl, [lower alkoxycarbonylamino]phenyl, [lower alkoxyglyoxyloylamino]phenyl, [cyclo(lower)alkyloxycarbonylamino]phenyl, [cyclo(lQwer)alkylcarbonylamino]phenyl, [cyclo(lower)alkylidene(lower)alkanoylamino]phenyl, [benzoylamino]phenyl, [mono(or di)(lower alkyl)benzoylamino]phenyl, [mono(or di)halobenzoylamino]phenyl, [di(lower alkoxy)benzoylamino]phenyl, [bis(lower alkoxycarbonyl)benzoylamino]phenyl, [mono(or di)nitrobenzoylamino]phenyl, [hydroxybenzoylamino]phenyl, [lower alkanoyloxybenzoylamino]phenyl, [bis[trihalo(lower)alkyl]benzoylamino]phenyl, phenyl having benzoylamino substituted with lower alkoxycarbonyl and nitro, phenyl having benzoylamino substituted with lower alkoxy and cyclo(lower)alkyloxy, [phenylbenzoylamino]phenyl, [[lower alkoxycarbonyl(lower)alkenyl]benzoylamino]phenyl, [[benzoylamino]benzoylamino]phenyl, [pyrimidinyloxybenzoylamino]phenyl, [[nitropyridylamino]benzoylamino]phenyl, [naphthoylamino]phenyl, [hydroxynaphthoylamino]phenyl, [[lower alkanoyloxynaphthoyl]amino]phenyl, [[lower alkoxycarbonylnaphthoyl]amino]phenyl, [phenylsulfonylamino]phenyl, [dihalophenylsulfonylamino]phenyl, [phenyl(lower)alkylsulfonylamino]phenyl, [cyclo(lower)alkylcarbonylamino]phenyl, [mono(or di)phenyl(lower)alkanoylamino]phenyl, [naphthyl(lower)alkanoylamino]phenyl, [lower alkadienoylamino]phenyl, [furylcarbonylamino]phenyl, [pyridylcarbonylamino]phenyl, [dihalopyridylcarbonylamino]phenyl, [thienylcarbonylamino]phenyl, [indolinylcarbonylamino]phenyl, [quinolylcarbonylamino]phenyl, [tetrahydroquinolylcarbonylamino]phenyl, [benzofurylcarbonylamino]phenyl, [lower alkylindolylcarbonylamino]phenyl, [benzothienylcarbonylamino]phenyl, [methylenedioxybenzoylamino]phenyl, [morpholinylcarbonylamino]phenyl, [phenyl(lower)alkenoylamino]phenyl, [[lower alkylphenyl(lower)alkenoyl]amino]phenyl, [[mono(or di)halophenyl(lower)alkenoyl]amino]phenyl, [[lower alkoxycarbonylphenyl(lower)alkenoyl]amino]phenyl, [[nitrophenyl(lower)alkenoyl]amino]phenyl, [pyridyl(lower)alkenoylamino]phenyl, ureidophenyl, [lower alkylureido]phenyl, [phenylureido]phenyl, [[aminophenyl]ureido]phenyl, [[halophenylureido]phenyl, [[nitrophenyl]ureido]phenyl, [[lower alkoxyphenyl]ureido]phenyl, [[lower alkylthiophenyl]ureido]phenyl, [[mono(or di)(lower alkyl)phenyl]ureido]phenyl, [biphenylylureido]phenyl, [[carboxyphenyl]ureido]phenyl, [[lower alkoxycarbonylphenyl]uredio]phenyl, [[di(lower)alkylaminophenyl]ureido]phenyl, [[trihalo(lower)alkylphenyl]ureido]phenyl, [[dihalophenyl]ureido]phenyl, [naphthylureido]phenyl, [phenylsulfonylureido]phenyl, [phenyl(lower)alkylureido]phenyl, [cyclo(lower)alkylureido]phenyl, [thiazolylureido]phenyl, [pyridylureido]phenyl, [quinolylureido]phenyl, [morpholinylureido]phenyl, [N-phenyl-N-lower alkylureido]phenyl, [phenyl(thioureido)]phenyl, [naphthyl(thioureido)]phenyl, [benzoyl(thioureido)]phenyl, [lower alkylamino]phenyl, [N-lower alkanoyl-N-lower alkylamino]phenyl, [N-benzoyl-N-lower alkylamino]phenyl, [N-phenylcarbamoyl-N-lower alkylamino]phenyl, [N-lower alkoxycarbonylphenyl(lower)alkenoyl-N-lower alkylamino]phenyl, [lower alkylthiazolylamino]phenyl, [phenylthiazolylamino]phenyl, [pyrimidinylamino]phenyl, lower alkanoylphenyl, carbamoylphenyl, [lower alkylcarbamoyl]phenyl, [phenylcarbamoyl]phenyl, [dihalophenylcarbamoyl]phenyl, [N-dihalophenyl-N-lower alkylcarbamoyl]phenyl, benzoylphenyl, [lower alkoxybenzoyl]phenyl, morpholinylcarbonylphenyl, indolizinylcarbonylphenyl, [phenylcarbamoyl(lower)alkyl]phenyl, [naphthylcarbamoyl(lower)alkyl]phenyl, phenylphenyl, [[lower alkoxycarbonyl(lower)alkenyl]phenyl]phenyl,, biphenylylphenyl, phenyl having phenyl substituted with lower alkoxy and cyclo(lower)alkyloxy, [halophenyl]phenyl, [carboxyphenyl]phenyl, [lower alkoxycarbonylphenyl]phenyl, [aminophenyl]phenyl, [[lower alkanoylamino]phenyl]phenyl, [[benzoylamino]phenyl]phenyl, [[carboxybenzoylamino]phenyl]phenyl, [[mono(or bis)(lower alkylsulfonyl)amino]phenyl]phenyl, [[trihalo(lower)alkanoylamino]phenyl]phenyl, [[lower alkoxycarbonylamino]phenyl]phenyl, [[phenoxycarbonylamino]phenyl]phenyl, [[carboxy(lower)alkanoylamino]phenyl]phenyl, [[lower alkoxycarbonyl(lower)alkanoylamino]phenyl]phenyl, [[lower alkoxycarbonyl(lower)alkenoylamino]phenyl]phenyl, [[cyclo(lower)alkylcarbonylamino]phenyl]phenyl, [[lower alkylglyoxyloylamino]phenyl]phenyl, [[dihalophenylsulfonylamino]phenyl]phenyl, [[phenyl(lower)alkenoylamino]phenyl]phenyl, phenylphenyl substituted with (lower)alkenoylamino having phenyl and carboxy, [[pyridyl(lower)alkenoylamino]phenyl]phenyl, [[quinoxalinylcarbonylamino]phenyl]phenyl, [[benzothienylcarbonylamino]phenyl]phenyl, [[lower alkylcarbamoylamino]phenyl]phenyl, [[phenylcarbamoylamino]phenyl]phenyl, [[naphthylcarbamoyl]phenyl]phenyl, naphthylphenyl, [lower alkoxynaphthyl]phenyl, [phenyl(lower)alkyl]phenyl, [naphthyl(lower)alkyl]phenyl, [phenyl(lower)alkenyl]phenyl, [dihalophenyl(lower)alkenyl]phenyl, [naphthyl(lower)alkenyl]phenyl, [benzoyl(lower)alkenyl]phenyl, [lower alkoxycarbonyl(lower)alkenyl]phenyl, [cyano(lower)alkenyl]phenyl, [pyridyl(lower)alkenyl]phenyl, [(halopyridyl)(lower)alkenyl]phenyl, [pyrimidinyl(lower)alkenyl]phenyl, [quinolyl(lower)alkenyl]phenyl, pyridylphenyl, thienylphenyl, halothienylphenyl, pyrrolylphenyl, [dihalopyrrolyl]phenyl, [cyanopyrrolyl]phenyl, [lower alkoxycarbonylpyrrolyl]phenyl, [dioxopyrrolidinyl]phenyl, indolylphenyl, [lower alkoxycarbonylindolyl]phenyl, [lower alkanoylindolyl]phenyl, quinolylphenyl, isoquinolylphenyl, imidazolylphenyl, [aminothiazolyl]phenyl, [pyridylthiazolyl]phenyl, benzothiazolylphenyl, triazolylphenyl, pyrimidinyloxyphenyl, [phenylpyrimidinyloxy]phenyl, phenyl having halogen and amino, phenyl having halogen and (halophenyl)ureido, phenyl having halogen and (lower alkoxypheny l)ureido, phenyl having halogen and lower alkanoylamino, bis(lower alkoxycarbonyl)phenyl, phenyl having lower alkoxycarbonyl and amino, phenyl having lower alkoxycarbonyl and lower alkanoylamino, phenyl having lower alkoxycarbonyl and naphthoylamino, phenyl having halogen and naphthoylamino, phenyl having cyclo(lower)alkyloxy and lower alkoxy, naphthyl or pyridyl, and
R3 is hydrogen, lower alkoxy or phenylthio.
The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.
A mixture of 2-chloro-3-nitropyridine (1.59 g) and m-toluidine (1.07 g) was heated at 100xc2x0 C. for 20 minutes. The mixture was cooled and dissolved in ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate, 4:1) to afford 3-nitro-2-[(m-tolyl)amino]pyridine (834 mg) as an orange solid.
NMR (CDCl3, xcex4): 2.49 (3H, s), 6.83 (1H, dd, J=5 Hz, 8 Hz), 7.02 (1H, d, J=8 Hz), 7.29 (1H, t, J=8 Hz), 7.4-7.5 (2H, m), 8.45-8.6 (2H, m), 10.08 (1H, br s)
The following compounds were obtained according to a similar manner to that of Preparation 1.
(1) 3-Nitro-2-[(pyridin-3-yl)amino]pyridine
NMR (CDCl3, xcex4): 6.93 (1H, dd, J=5 Hz, 8 Hz), 7.35 (1H, dd, J=5 Hz, 8 Hz), 8.17 (1H, dt, J=8 Hz, 1.5 Hz), 8.42 (1H, dd, J=1.5 Hz, 5 Hz), 8.45-8.6 (2H, m), 8.87 (1H, d, J=3 Hz), 10.10 (1H, s)
(2) 3-Nitro-2-[(pyridin-2-yl)amino]pyridine
NMR (CDCl3, xcex4): 6.96 (1H, dd, J=5 Hz, 8 Hz), 7.05 (1H, m), 7.23 (1H, dt, J=1.5 Hz, 8 Hz), 8.3-8.65 (4H, m)
(3) 2-(1-Naphthyl)amino-3-nitropyridine
NMR (CDCl3, xcex4): 6.82 (1H, dd, J=1.5 Hz, 8 Hz), 7.45-7.65 (3H, m), 7.79 (1H, d, J=8 Hz), 7.85-8.1 (4H, m), 8.41 (1H, dd, J=1.5 Hz, 5 Hz), 8.48 (1H, dd, J=1.5 Hz, 8 Hz)
(4) 2-(3-Ethoxycarbonylphenyl)amino-3-nitropyridine
NMR (CDCl3, xcex4): 1.42 (3H, t, J=7 Hz), 4.41 (2H, q, J=7 Hz), 6.89 (1H, dd, J=5 Hz, 8 Hz), 7.48 (1H, t, J=8 Hz), 7.8-8.0 (2H, m), 8.28 (1H, s), 8.45-8.6 (2H, m), 10.17 (1H, br s)
(5) 2-(4-Methoxycarbonylphenyl)amino-3-nitropyridine
NMR (CDCl3, xcex4): 3.93 (3H, s), 6.96 (1H, dd, J=5 Hz, 8 Hz), 7.82 (2H, d, J=9 Hz), 8.08 (2H, d, J=9 Hz), 8.5-8.6 (2H, m)
(6) 2-(4-Methoxycarbonylmethylphenyl)amino-3-nitropyridine
NMR CDCl3, xcex4): 3.64 (2H, s), 3.71 (3H, s), 6.83 (1H, dd, J=5 Hz, 8 Hz), 7.32 (2H, d, J=9 Hz), 7.62 (2H, d, J=9 Hz), 8.45-8.6 (2H, m), 10.11 (1H, br s)
(7) 2-(3-Methoxycarbonylmethylphenyl)amino-3-nitropyridine
NMR (CDCl3, xcex4): 3.68 (2H, s), 3.72 (3H, s), 6.85 (1H, dd, J-5 Hz, 8 Hz), 7.11 (1H, d, J=8 Hz), 7.37 (1H, t, J=8 Hz), 7.60 (2H, d, J=8 Hz), 8.45-8.6 (2H, m), 10.12 (1H, br s)
(8) 2-(4-Acetylphenyl)amino-3-nitropyridine
NMR CDCl3, xcex4): 2.61 (3H, s), 6.95 (1H, dd, J=5 Hz, 8 Hz), 7.83 (2H, d, J=9 Hz), 8.00 (2H, d, J=9 Hz), 8.5-8.6 (2H, m)
(9) 2-(3-Acetylphenyl)amino-3-nitropyridine
NMR (CDCl3, xcex4): 2.65 (3H, s), 6.90 (1H, dd, J=5 Hz, 8 Hz), 7.50 (1H, t, J=8 Hz), 7.77 (1H, d, J=8 Hz), 7.90 (1H, dd, J=1.5 Hz, 8 Hz), 8.25 (1H, s), 8.45-8.6 (2H, m), 10.19 (1H, br s)
(10) 2-(3-Fluorophenyl)amino-3-nitropyridine
NMR (CDCl3, xcex4): 6.8-6.95 (2H, m), 7.25-7.4 (2H, m), 7.73 (1H, m), 8.5-8.6 (2H, m), 10.19 (1H, br s)
(11) 2-(3-Hydroxyphenyl)amino-3-nitropyridine
NMR (DMSO-d6, xcex4): 6.55 (1H, m), 6.95-7.25 (4H, m), 8.5-8.6 (2H, m), 9.48 (1H, s), 9.88 (1H, s)
(12) 2-(4-Methoxyphenyl)amino-3-nitropyridine
NMR (CDCl3, xcex4): 3.83 (3H, s), 6.78 (1H, dd, J=5 Hz, 8 Hz), 6.95 (2H, d, J=9 Hz), 7.48 (2H, d, J=9 Hz), 8.45 (1H, dd, J=1.5 Hz, 5 Hz), 8.51 (1H, dd, J=1.5 Hz, 8 Hz), 9.97 (1H, br s)
(13) 2-(3-Methoxyphenyl)amino-3-nitropyridine
NMR (CDCl3, xcex4): 3.85 (3H, s), 6.74 (1H, m), 6.87 (1H, dd, J=5 Hz, 8 Hz), 7.18 (1H, m), 7.25-7.4 (2H, m), 8.45-8.6 (2H, m), 10.13 (1H, br s)
A mixture of 3-nitro-2-[(m-tolyl)amino]pyridine (825 mg) and 10% palladium carbon (0.3 g) in ethanol (15 ml) and 1,4-dioxane (15 ml) was stirred under hydrogen (3 atm) at room temperature for 30 minutes. The catalyst was removed and the solvent was evaporated. The solids were collected and washed with isopropyl ether to give 3-amino-2-[(m-tolyl)amino]pyridine (660 mg).
NMR (CDCl3, xcex4): 3.15 (2H, br s), 6.18 (1H, br s), 6.77 (1H, dd, J=5 Hz, 8 Hz), 6.95-7.3 (5H, m), 7.83 (1H, dd, J=1.5 Hz, 5 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 3.
(1) 3-Amino-2-[(pyridin-3-yl)amino]pyridine
NMR (DMSO-d6, xcex4): 5.12 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, dd, J=1.5 Hz, 8 Hz), 7.24 (1H, dd, J=5 Hz, 8 Hz), 7.50 (1H, dd, J=1.5 Hz, 5 Hz), 7.95 (1H, s), 8.0-8.15 (2H, m), 8.76 (1H, d, J=3 Hz)
(2) 3-Amino-2-[(pyridin-2-yl)amino]pyridine
NMR (DMSO-d6, xcex4): 5.23 (2H, s), 6.74 (1H, dd, J=5 Hz, 8 Hz), 6.83 (1H, m), 6.98 (1H, dd, J=1.5 Hz, 8 Hz), 7.5-7.7 (2H, m), 8.00 (1H, d, J=8 Hz), 8.18 (1H, m), 8.39 (1H, s)
(3) 3-Amino-2-[(1-naphthyl)amino]pyridine
NMR (DMSO-d6, xcex4): 5.12 (2H, s), 6.64 (1H, dd, J=5 Hz, 8 Hz), 6.98 (1H, dd, J=1.5 Hz, 8 Hz), 7.35-7.65 (6H, m), 7.76 (1H, s), 7.90 (1H, m), 8.05 (1H, m)
(4) 2-(3-Acetamidophenyl)amino-3-aminopyridine
NMR (DMSO-d6, xcex4): 2.03 (3H, s), 5.09 (2H, s), 6.63 (1H, dd, J=5 Hz, 8 Hz), 6.89 (1H, dd, J=1.5 Hz, 8 Hz), 7.0-7.25 (2H, m), 7.33 (1H, m), 7.49 (1H, dd, J=1.5 Hz, 5 Hz), 7.71 (1H, s), 7.87 (1H, s), 9.80 (1H, s)
(5) 3-Amino-2-[(3-ethoxycarbonylphenyl)amino]pyridine
NMR (DMSO-d6, xcex4): 1.33 (3H, t, J=7 Hz), 4.31 (2H, q, J=7 Hz), 5.12 (2H, s), 6.68 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, dd, J=1.5 Hz, 8 Hz), 7.3-7.5 (2H, m), 7.52 (1H, dd, J=1.5 Hz, 5 Hz), 7.95-8.1 (2H, m), 8.17 (1H, s)
(6) 3-Amino-2-[(4-methoxycarbonylphenyl)amino]pyridine
NMR (DMSO-d6, xcex4): 3.86 (3H, s), 5.19 (2H, s), 6.74 (1H, dd, J=5 Hz, 8 Hz), 6.98 (1H, dd, J=1.5 Hz, 8 Hz), 7.58 (1H, dd, J=1.5 Hz, 5 Hz), 7.70 (2H, d, J=9 Hz), 7.83 (2H, d, J=9 Hz), 8.28 (1H, s)
(7) 3-Amino-2-[(4-methoxycarbonylmethylphenyl)amino]pyridine
NMR (DMSO-d6, xcex4): 3.58 (2H, s), 3.61 (3H, s), 5.07 (2H, s), 6.61 (1H, dd, J=5 Hz, 8 Hz), 6.89 (1H, dd, J=1.5 Hz, 8 Hz), 7.11 (2H, d, J=9 Hz), 7.49 (1H, dd, J=1.5 Hz, 5 Hz), 7.57 (2H, d, J=9 Hz), 7.70 (1H, s)
(8) 3-Amino-2-[(3-methoxycarbonylmethylphenyl)amino]pyridine
NMR (CDCl3, xcex4): 3.41 (2H, br s), 3.61 (2H, s), 3.69 (3H, s), 6.21 (1H, br s), 6.78 (1H, dd, J=5 Hz, 8 Hz), 6.87 (1H, m), 7.01 (1H, dd, J=1.5 Hz, 8 Hz), 7.15-7.3 (3H, m), 7.85 (1H, dd, J=1.5 Hz, 5 Hz)
(9) 2-(4-Acetylphenyl)amino-3-aminopyridine
NMR (DMSO-d6, xcex4): 2.49 (3H, s), 5.19 (2H, s), 6.75 (1H, dd, J=5 Hz, 8 Hz), 6.98 (1H, dd, J=1.5 Hz, 8 Hz), 7.57 (1H, dd, J=1.5 Hz, 5 Hz), 7.69 (2H, d, J=9 Hz), 7.86 (2H, d, J=9 Hz), 8.27 (1H, s)
(10) 2-(3-Acetylphenyl)amino-3-aminopyridine
NMR (DMSO-d6, xcex4): 2.57 (3H, s), 5.11 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, dd, J=1.5 Hz, 8 Hz), 7.2-7.55 (3H, m), 7.95-8.05 (2H, m), 8.13 (1H, s)
(11) 3-Amino-2-[(3-fluorophenyl)amino]pyridine
NMR (DMSO-d6, xcex4): 5.11 (2H, s), 6.55-6.75 (2H, m), 6.93 (1H, dd, J=1.5 Hz, 8 Hz), 7.15-7.35 (2H, m), 7.54 (1H, dd, J=1.5 Hz, 5 Hz), 7.72 (1H, dt, J=13 Hz, 1.5 Hz), 7.98 (1H, s)
(12) 3-Amino-2-[(3-hydroxyphenyl)amino]pyridine
NMR (DMSO-d6, xcex4): 5.12 (2H, br s), 6.27 (1H, m), 6.61 (1H, dd, J=1.5 Hz, 8 Hz), 6.85-7.05 (3H, m), 7.71 (1H, s), 7.49 (1H, dd, J=1.5 Hz, 5 Hz), 7.63 (1H, s), 9.12 (1H, s)
(13) 3-Anino-2-[(4-methoxyphenyl)amino]pyridine
NMR CDCl3, xcex4): 3.07 (2H, br s), 3.79 (3H, s), 6.19 (1H, br s), 6.70 (1H, dd, J=5 Hz, 8 Hz), 6.87 (2H, d, J=9 Hz), 7.23 (2H, d, J=9 Hz), 7.78 (1H, dd, J=1.5 Hz, 5 Hz)
(14) 3-Amino-2-[(3-methoxyphenyl)amino]pyridine
NMR (CDCl3, xcex4): 3.42 (2H, br s), 3.79 (3H, s), 6.21 (1H, s), 6.51 (1H, m), 6.75-6.85 (2H, m), 6.92 (1H, m), 7.02 (1H, dd, J=1.5 Hz, 8 Hz), 7.18 (1H, t, J=8 Hz), 7.85 (1H, dd, J=1.5 Hz, 5 Hz)
A mixture of 2-chloro-3-nitropyridine (6.12 g), 3xe2x80x2-aminoacetanilide (5.80 g) and potassium carbonate (5.34 g) in toluene (50 ml) was refluxed for 5 hours. The mixture was cooled, and the solids were collected and washed with water, ethanol and isopropyl ether successively to give 2-(3-acetamidophenyl)amino-3-nitropyridine (5.88 g) as an orange solid.
NMR (DMSO-d6, xcex4): 2.06 (3H, s), 6.99 (1H, dd, J=5 Hz, 8 Hz), 7.2-7.4 (3H, m), 7.91 (1H, s), 8.5-8.6 (2H, m), 9.93 (1H, s), 9.99 (1H, s)
To a mixture of ethyl 3-aminobenzoate (996 mg) and triethylamine (0.85 ml) in dichloromethane (10 ml) was added benzoyl chloride (0.70 ml). The mixture was stirred at room temperature for 15 minutes, poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give ethyl 3-benzoylaminobenzoate (1.36 g).
NMR (DMSO-d6, 300 MHz, xcex4): 1.33 (3H, t, J=7 Hz), 4.33 (2H, q, J=7 Hz), 7.45-7.75 (5H, m), 7.98 (2H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz)
To a suspension of sodium hydride (60% in oil, 5.19 g) in N,N-dimethylformamide (30 ml) was added a solution of 3xe2x80x2-nitroacetanilide (214 mg) in N,N-dimethylformamide (30 ml) at 0xc2x0 C. The mixture was stirred at room temperature for 30 minutes, then iodomethane (3.59 ml) was added. After 30 minutes, 1N hydrochloric acid was poured into the mixture and extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-methyl-3xe2x80x2-nitroacetanilide (4.64 g).
NMR (DMSO-d6, 200 MHz, xcex4): 1.92 (3H, s), 3.25 (3H, s), 7.65-7.9 (2H, m), 8.1-8.3 (2H, m)
A mixture of ammonium thiocyanate (2.79 g) and benzoyl chloride (3.86 ml) in acetone (30 ml) was refluxed for 5 minutes. Then a solution of 3xe2x80x2-aminoacetanilide (5.00 g) in acetone (40 ml) was added thereto. The mixture was poured into water, and the resulting precipitate was separated by filtration. The crystals were heated at 50xc2x0 C. for 3 hours with 1N sodium hydroxide (150 ml) solution. The mixture was poured into a mixture of ethyl acetate and water, and the resulting precipitate was collected and washed with ethyl acetate and water to give N-(3-acetylaminophenyl)thiourea (4.22 g).
NMR (DMSO-d6, 300 MHz, xcex4): 2.03 (3H, s), 7.12 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.62 (1H, s), 9.68 (1H, s), 9.95 (1H, s)
A mixture of 3-nitroaniline (6.14 g), 2-chloropyrimidine (4.85 g) and potassium carbonate (6.15 g) in dimethylsulfoxide (50 ml) was heated at 170xc2x0 C. for 5 hours. The mixture was cooled and poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-nitrophenylamino)pyrimidine (1.92 g).
NMR (DMSO-d6, 300 MHz, xcex4): 6.97 (1H, t, J=5 Hz), 7.57 (1H, t, J=8 Hz), 7.78 (1H, d, J=8 Hz), 8.09 (1H, d, J=8 Hz), 8.58 (2H, d, J=5 Hz), 8.85 (1H, s)
A mixture of 3-nitrophenol (6.85 g), 2-chloropyrimidine (5.13 g) and potassium carbonate (6.81 g) in dimethylsulfoxide (50 ml) was heated at 150xc2x0 C. for 30 minutes. The mixture was cooled and poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-nitrophenoxy)pyrimidine (7.41 g).
NMR (DMSO-d6, 300 MHz, xcex4): 7.35 (1H, t, J=5 Hz), 7.7-7.8 (2H, m), 8.1-8.2 (2H, m), 8.69 (2H, d, J=5 Hz)
A mixture of methyl 3-hydroxybenzoate (3.4 g), 2-chloropyrimidine (2.29 g) and potassium carbonate (3.04 g) in dimethylsulfoxide (30 ml) was stirred at 150xc2x0 C. for 1 hour. The mixture was poured into a mixture of ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give methyl 3-(pyrimidine-2-yl)oxybenzoate (3.66 g).
NMR (CDC13, 300 MHz, xcex4): 3.92 (3H, s), 7.07 (1H, t, J=5 Hz), 7.41 (1H, m), 7.52 (1H, t, J=8 Hz), 7.88 (1H, t, J=1.5 Hz), 7.96 (1H, d, J=8 Hz), 8.58 (2H, d, J=5 Hz)
The following compound was obtained according to similar manners to those of Preparations 10 and 11.
2-(3-Nitrophenoxy)-4-phenylpyrimidine
NMR (DMSO-d6, 300 MHz, xcex4): 7.5-7.65 (3H, m), 7.75-7.9 (2H, m), 7.93 (1H, d, J=5 Hz), 8.1-8.25 (4H, m), 8.73 (1H, d, J=5 Hz)
To a solution of iodobenzene (3.53 ml) in ether (10 ml) was added n-butyllithium (1.6M in hexane, 20 ml), and the mixture was stirred at room temperature for 20 minutes. The above solution was added to a solution of 2-chloropyrimidine (3.52 g) in ether (90 ml) at xe2x88x9230xc2x0 C. The mixture was stirred at xe2x88x9230xc2x0 C. for 30 minutes and then at 0xc2x0 C. for 30 minutes, quenched with a solution of acetic acid (1.83 ml) and water (0.31 ml) in tetrahydrofuran (6 ml), and treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (7.26 g) in tetrahydrofuran (30 ml). The mixture was stirred at 0xc2x0 C. for 5 minutes, cooled to 0xc2x0 C., treated with a cold aqueous solution of sodium hydroxide (3M, 9.2 ml), and stirred at 0xc2x0 C. for 5 minutes. The organic phase was separated, washed with water and brine, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate, 7:3) to afford 2-chloro-4-phenylpyrimidine (3.39 g) as a solid.
NMR (DMSO-d6, 300 MHz, xcex4): 7.55-7.7 (3H, m), 8.15-8.25 (3H, m), 8.83 (1H, d, J=5 Hz)
A mixture of 2-bromo-3xe2x80x2-nitroacetophenone (12.2 g) and thiourea (3.81 g) in ethanol (100 ml) was stirred at room temperature for 15 minutes. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-amino-4-(3-nitrophenyl)thiazole (10.21 g).
NMR (DMSO-d6, 300 MHz, xcex4): 7.24 (2H, s), 7.36 (1H, s), 7.67 (1H, t, J=8 Hz), 8.10 (1H, dt, J=8 Hz, 1.5 Hz), 8.24 (1H, dt, J=8 Hz, 1.5 Hz), 8.62 (1H, t, J=1.5 Hz)
A mixture of 2-bromo-3xe2x80x2-nitroacetophenone (3.66 g) and 3-thiocarbamoylpyridine (2.07 g) in ethanol (40 ml) was refluxed for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 4-(3-nitrophenyl)-2-(pyridin-3-yl)thiazole (2.91 g).
NMR (DMSO-d6, 300 MHz, xcex4): 7.55 (1H, m), 7.78 (1H, t, J=8 Hz), 8.22 (1H, d, J=8 Hz), 8.41 (1H, m), 8.50 (1H, d, J=8 Hz), 8.59 (1H, s), 8.70 (1H, dd, J=1.5 Hz, 5 Hz), 8.83 (1H, s), 9.22 (1H, d, J=1.5 Hz)
A mixture of 2-bromo-3xe2x80x2-nitroacetophenone (4.88 g.) and formamide (50 ml) was stirred at 185xc2x0 C. for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with ethyl acetate to give 4-(3-nitrophenyl)imidazole (2.32 g).
NMR (DMSO-d6, 300 MHz, xcex4): 7.63 (1H, t, J=8 Hz), 7.78 (1H, s), 7.90 (1H, s), 8.02 (1H, d, J=8 Hz), 8.21 (1H, d, J=8 Hz), 8.58 (1H, s), 12.36 (1H, br s)
A mixture of 3-nitrobenzoyl chloride (3.71 g), anisole (2.0 ml) and aluminum chloride (2.67 g) in dichloromethane (50 ml) was refluxed for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with ethyl acetate to give 1-(3-nitrobenzoyl)-4-methoxybenzene (955 mg).
NMR (DMSO-d6, 300 MHz, xcex4): 3.88 (3H, s), 7.12 (2H, d, J=8 Hz), 7.75-7.9 (3H, m), 8.12 (1H, d, J=8 Hz), 8.39 (1H, s), 8.48 (1H, m)
A mixture of 3-nitrobenzoyl chloride (4.50 g) and indolizine (2.84 g) in dichloromethane (30 ml) was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with ethyl acetate to give 3-(3-nitrobenzoyl)indolizine (4.51 g).
NMR (DMSO-d6, 300 MHz, xcex4): 6.74 (1H, d, J=5 Hz), 7.18 (1H, m), 7.35-7.45 (2H, m), 7.8-7.9 (2H, m), 8.09 (1H, d, J=8 Hz), 8.4-8.5 (2H, m), 9.85 (1H, d, J=7 Hz)
To a suspension of sodium hydride (60% in oil, 1.48 g) in N,N-dimethylformamide (40 ml) was added a solution of diethyl benzylphosphonate (7.69 g) in N,N-dimethylformamide (40 ml) at 0xc2x0 C. The mixture was stirred at room temperature for 30 minutes, then a solution of 3-nitrobenzaldehyde (5.09 g) was added thereto. After stirring at 50xc2x0 C. for 1 hour, the mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate 3 times. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give (E)-3-nitrostilbene (3.97 g).
NMR (CDCl3, 300 MHz, xcex4): 7.1-7.6 (8H, m), 7.80 (1H, d, J=8 Hz), 8.10 (1H, dd, J=1.5 Hz, 8 Hz), 8.38 (1H, s)
The following compounds were obtained according to a similar manner to that of Preparation 19.
(1) 2-((E)-3-Nitrostyryl)naphthalene
NMR (CDCl3, 300 MHz, xcex4): 7.25 (1H, d, J=16 Hz), 7.35-7.6 (4H, m), 7.7-7.95 (6H, m), 8.10 (1H, dd, J=1.5 Hz, 8 Hz), 8.41 (1H, s)
(2) (E)-3-Nitrostyryl phenyl ketone
NMR (CDCl3, 300 MHz, xcex4): 7.5-7.7 (5H, m), 7.86 (1H, d, J=16 Hz), 7.93 (1H, d, J=8 Hz), 8.06 (2H, d, J=8 Hz), 8.28 (1H, dd, J=1.5 Hz, 8 Hz), 8.52 (1H, s)
(3) (E)-3-(3-Nitrophenyl)propenonitrile
NMR (CDCl3, 300 MHz, xcex4): 6.07 (1H, d, J=16 Hz), 7.48 (1H, d, J=16 Hz), 7.64 (1H, t, J=8 Hz), 7.78 (1H, d, J=8 Hz), 8.25-8.4 (2H, m)
(4) (E)-Methyl 3-(3-nitrophenyl)propenoate
NMR (CDCl3, 300 MHz, xcex4): 3.84 (3H, s), 6.57 (1H, d, J=16 Hz), 7.59 (1H, t, J=8 Hz), 7.73 (1H, d, J=16 Hz), 7.83 (1H, d, J=8 Hz), 8.24 (1H, dd, J=1.5 Hz, 8 Hz), 8.39 (1H, t, J=1.5 Hz)
A mixture of N-methyl-31-nitroacetanilide (5.13 g) and 10% palladium carbon (0.6 g) in methanol (50 ml) and 1,4-dioxane (50 ml) and stirred under hydrogen (3 atm) at room temperature for 2 hours. The catalyst was removed by filtration and the solvent was evaporated. The resultant solid was collected and washed with isopropyl ether to give 3xe2x80x2-amino-N-methylacetanilide (4.06 g).
NMR (DMSO-d6, 200 MHz, xcex4): 1.78 (3H, s), 3.08 (3H, s), 5.28 (2H, s), 6.35-6.6 (3H, m), 7.05 (1H, t, J=8 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 21.
(1) 3-(Pyrimidin-2-yl)aminoaniline
NMR (DMSO-d6, 300 MHz, xcex4): 4.96 (2H, s), 6.28 (1H, m), 6.78 (1H, m), 6.8-6.95 (2H, m), 7.05 (1H, s), 8.42 (2H, d, J=5 Hz), 9.28 (1H, s)
(2) 3-(Pyrimidin-2-yl) oxyaniline
NMR (DMSO-d6, 300 MHz, xcex4): 5.23 (2H, s), 6.2-6.35 (2H, m), 6.43 (1H, d, J=8 MHz), 7.02 (1H, t, J=8 Hz), 7.23 (1H, t, J=5 Hz), 8.62 (2H, d, J=5 Hz)
(3) 3-(4-Phenylpyrimidin-2-yl)oxyaniline
NMR (DMSO-d6, 300 MHz, xcex4): 5.27 (2H, s), 6.3-6.5 (3H, m), 7.07 (1H, t, J=8 Hz), 7.45-7.65 (3H, m), 7.82 (1H, d, J=5 Hz), 8.05-8.2 (2H, m), 8.67 (1H, d, Jxe2x88x925 Hz)
A mixture of (E)-3-nitrostilbene (3.63 g), hydrochloric acid (35%, 10 ml) and iron powder (3.6 g) in ethanol (30 ml) was refluxed for 1 hour. The mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give (E)-3-aminostilbene (2.05 g).
NMR (DMSO-d6, 300 MHz, xcex4): 5.09 (2H, s), 6.49 (1H, d, J=8 Hz), 6.7-6.85 (2H, m), 7.0-7.15 (3H, m), 7.2-7.45 (3H, m), 7.58 (2H, d, J=8 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 23.
(1) 2-Amino-4-(3-aminophenyl)thiazole
NMR (DMSO-d6, 300 MHz, xcex4): 5.02 (2H, s), 6.45 (1H, m), 6.76 (1H, s), 6.9-7.05 (5H, m)
(2) 3-[2-(Pyridin-3-yl)thiazol-4-yl]aniline
NMR (DMSO-d6, 300 MHz, xcex4): 5.20 (2H, s), 6.58 (1H, d, J=8 Hz), 7.05-7.2 (2H, m), 7.30 (1H, s), 7.58 (1H, m), 8.05 (1H, s), 8.35 (1H, d, J=8 Hz), 8.68 (1H, d, J=5 Hz), 9.19 (1H, d, J=1.5 Hz)
(3) 3-(Imidazol-4-yl)aniline
NMR (DMSO-d6, 300 MHz, xcex4): 4.96 (2H, s), 6.38 (1H, d, J=8 Hz), 6.85-7.1 (3H, m), 7.40 (1H, s), 7.64 (1H, s), 12.04 (1H, br s)
(4) 3-Amino-4xe2x80x2-methoxybenzophenone
NMR (DMSO-d6, 300 MHz, xcex4): 3.84 (3H, s), 5.37 (2H, s), 6.75-6.85 (2H, m), 6.89 (1H, t, J=1.5 Hz), 7.07 (2H, dt, J=8 Hz, 1.5 Hz), 7.16 (1H, t, J=8 Hz), 7.72 (2H, dt, J=8 Hz, 1.5 Hz)
(5) 3-(3-Indolizinylcarbonyl)aniline
NMR (DMSO-d6, 300 MHz, xcex4): 5.32 (2H, s), 6.65 (1H, d, J=5 Hz), 6.75 (1H, m), 7.86 (1H, d, J=8 Hz), 6.97 (1H, s), 7.05-7.2 (2H, m), 7.25-7.4 (2H, m), 7.77 (1H, d, J=8 Hz), 9.81 (1H, d, J=7 Hz)
(6) 3-[(E)-2-(2-Naphthyl)vinyl]aniline
NMR (DMSO-d6, 300 MHz, xcex4): 5.09 (2H, s), 6.50 (1H, d, J=8 Hz), 6.75-6.85 (2H, m), 7.03 (1H, t, J=8 Hz), 7.23 (2H, s), 7-.4-7.55 (2H, m), 7.8-7.95 (4H, m), 7.98 (1H, s)
(7) (E)-3-Aminostyryl phenyl ketone
NMR (DMSO-d6, 300 MHz, xcex4): 5.21 (2H, s), 6.68 (1H, d, J=8 Hz), 6.95-7.15 (3H, m), 7.5-7.8 (5H, m), 8.10 (2H, d, J=8 Hz)
(8) (E)-3-(3-Aminophenyl)propenonitrile
NMR (DMSO-d6, 300 MHz, xcex4): 5.26 (2H, s), 6.23 (1H, d, J=16 Hz), 6.64 (1H, d, J=8 Hz), 6.73 (1H, s), 6.79 (1H, d, J=8 Hz), 7.08 (1H, t, J=8 Hz), 7.48 (1H, d, J=16 Hz)
(9) (E)-Methyl 3-(3-aminophenyl)propenoate
NMR (DMSO-d6, 300 MHz, xcex4): 3.72 (3H, s), 5.19 (2H, S), 6.41 (1H, d, J=16 Hz), 6.64 (1H, dd, J=1.5 Hz, 8 Hz), 6.75-6.85 (2H, m), 7.06 (1H, t, J=8 Hz), 7.48 (1H, d, J=16 Hz)
A mixture of N-(3-acetylaminophenyl)thiourea (0.84 g) and 2-bromoacetophenone (0.84 g) in ethanol (10 ml) was refluxed for 15 minutes. After evaporation of the solvent, 3N hydrochloric acid was added thereto and the mixture was refluxed for 30 minutes. The mixture was made basic with sodium bicarbonate and extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 3-(4-phenylthiazol-2-yl)aminoaniline (0.88 g).
NMR (DMSO-d6, 300 MHz, xcex4): 5.11 (2H, s), 6.20 (1H, d, J=8 Hz), 6.82 (1H, m), 6.9-7.0 (2H, m), 7.25-7.35 (2H, m), 7.42 (2H, t, J=8 Hz), 7.93 (2H, d, J=8 Hz)
The following compound was obtained according to a similar manner to that of Preparation 25.
3-(4-Methylthiazol-2-yl)aminoaniline
NMR (DMSO-d6, 300 MHz, xcex4): 2.19 (3H, s), 5.02 (2H, s), 6.15 (1H, d, J=8 Hz), 6.37 (1H, s), 6.65-6.8 (2H, m), 6.90 (1H, t, J=8 Hz), 9.73 (1H, s)
A mixture of 2-chloro-3-nitropyridine (1.96 g) and 3xe2x80x2-amino-N-methylacetanilide (2.03 g) in toluene (20 ml) was refluxed for 7 hours. The mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[3-(N-methylacetamido)phenylamino]-3-nitropyridine (872 mg).
NMR (DMSO-d6, 200 MHz, xcex4): 1.85 (3H, s), 3.18 (3H, s), 7.0-7.15 (2H, m), 7.42 (1H, t, J=8 Hz), 7.66 (2H, m), 8.5-8.6 (2H, m), 10.01 (1H, s)
A mixture of 2-chloro-3-nitropyridine (2.27 g), 3-chloroaniline (1.5 ml) and potassium carbonate (2.2 g) in 1,4-dioxane (30 ml) was refluxed for 20 hours. The insoluble materials were removed by filtration and the filtrate was concentrated. Silica gel column chromatography (chloroform-methanol, 50:1) afforded 2-(3-chlorophenylamino)-3-nitropyridine (404 mg) as an orange solid.
NMR (CDCl3, 300 MHz, xcex4): 6.90 (1H, dd, J=5 Hz, 8 Hz), 7.15 (1H, dt, J=8 Hz, 1.5 Hz), 7.31 (1H, t, J=8 Hz), 7.45 (1H, dt, J=8 Hz, 1.5 Hz), 7.88 (1H, t, J=1.5 Hz), 8.5-8.6 (2H, m), 10.14 (1H, s)
The following compounds were obtained according to similar manners to those of Preparations 1, 5 and 28.
(1) 2-(3-Cyanophenylamino)-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 6.97 (1H, dd, J=5 Hz, 8 Hz), 7.4-7.55 (2H, m), 7.7-7.8 (1H, m), 8.32 (1H, s), 8.5-8.65 (2H, m), 10.22 (1H, s)
(2) 2-(3-Biphenylylamino)-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 6.85 (1H, dd, J=5 Hz, 8 Hz), 7.2-7.5 (5H, m), 7.55-7.7 (3H, m), 7.86 (1H, t, J=1.5 Hz), 8.45-8.6 (2H, m), 10.19 (1H, s)
(3) 3-Nitro-2-[3-(4-phenylthiazol-2-yl)aminophenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.05 (1H, dd, J=5 Hz, 8 Hz), 7.21 (1H, d, J=8 Hz), 7.25-7.5 (6H, m), 7.92 (2H, d, J=8 Hz), 8.37 (1H, s), 8.5-8.6 (2H, m)
(4) 3-Nitro-2-[3-(4-methylthiazol-2-yl)aminophenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 2.22 (3H, s), 6.45 (1H, s), 6.99 (1H, dd, J=5 Hz, 8 Hz), 7.17 (1H, d, J=8 Hz), 7.27 (1H, t, J=8 Hz), 7.41 (1H, d, J=8 Hz), 8.01 (1H, s), 8.5-8.6 (2H, m)
(5) 3-Nitro-2-[3-(pyrimidin-2-yl)aminophenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 6.84 (1H, t, J=5 Hz), 6.98 (1H, m), 7.2-7.3 (2H, m), 7.54 (1H, m), 8.05 (1H, s), 8.45-8.55 (4H, m), 9.67 (1H, s)
(6) 3-Nitro-2-[3-(pyrimidin-2-yl)oxyphenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 6.9-7.5 (2H, m), 7.28 (1H, t, J=5 Hz), 7.41 (1H, t, J=8 Hz), 7.53 (1H, d, J=8 Hz), 7.66 (1H, t, J=1.5 Hz), 8.5-8.6 (2H, m), 8.66 (2H, d, J=5 Hz)
(7) 3-Nitro-2-[3-[(4-phenylpyrimidin-2-yl)oxy]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 6.95-7.1 (2H, m), 7.43 (1H, t, J=8 Hz), 7.5-7.65 (4H, m), 7.74 (1H, t, J=1.5 Hz), 7.87 (1H, d, J=5 Hz), 8.1-8.2 (2H, m), 8.45-8.6 (2H, m), 8.69 (1H, d, J=5 Hz)
(8) 2-[3-(2-Aminothiazol-4-yl)phenylamino]-3-nitropyridine
NMR (DMSO-d6, 300 MHz, xcex4): 6.9-7.1 (4H, m), 7.36 (1H, t, J=8 Hz), 7.55-7.65 (2H, m), 7.98 (1H, s), 8.5-8.6 (2H, m), 9.99 (1H, s)
(9) 3-Nitro-2-[3-[2-(pyridin-3-yl)thiazol-4-yl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.01 (1H, m), 7.48 (1H, t, J=8 Hz), 7.57 (1H, m), 7.74 (1H, d, J=8 Hz), 7.84 (1H, d, J=8 Hz), 8.29 (1H, s), 8.39 (1H, dd, J=1.5 Hz, 8 Hz), 8.5-8.6 (2H, m), 8.69 (1H, d, J=5 Hz), 9.22 (1H, s), 10.05 (1H, s)
(10) 2-[3-(Imidazol-4-yl)phenylamino]-3-nitropyridine
NMR (DMSO-d6, 300 MHz, xcex4): 6.98 (1H, dd, J=5 Hz, 8 Hz), 7.3-7.75 (4H, m), 7.99 (1H, s), 8.5-8.6 (2H, m), 9.99 (1H, s), 12.18 (1H, br s)
(11) 2-[3-(4-Methoxybenzoyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 3.91 (3H, s), 6.88 (1H, dd, J=5 Hz, 8 Hz), 6.98 (2H, dt, J=8 Hz, 1.5 Hz), 7.45-7.6 (2H, m), 7.8-7.95 (3H, m), 8.09 (1H, s), 8.50 (1H, d, J=5 Hz), 8.55 (1H, d, J=8 Hz), 10.20 (1H, s)
(12) 2-[3-(3-Indolizinylcarbonyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 6.55 (1H, d, J=5 Hz), 6.86 (1H, dd, J=5 Hz, 8 Hz), 6.96 (1H, t, J=8 Hz), 7.22 (1H, t, J=8 Hz), 7.45-7.65 (4H, m), 7.79 (1H, d, J=8 Hz), 8.17 (1H, s), 8.5-8.6 (2H, m), 9.98 (1H, d, J=7 Hz), 10.22 (1H, s)
(13) 3-Nitro-2-[(E)-3-styrylphenylamino]pyridine
NMR (CDCl3, 300 MHz, xcex4): 6.85 (1H, dd, J=5 Hz, 8 Hz), 7.13 (2H, s), 7.20-7.45 (5H, m), 7.5-7.65 (3H, m), 7.78 (1H, s), 8.5-8.6 (2H, m), 10.16 (1H, s)
(14) 2-[3-[(E)-2-(2-Naphthyl)vinyl]phenylamino]-3-nitropyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.00 (1H, dd, J=5 Hz, 8 Hz), 7.35-7.55 (6H, m), 7.63 (1H, d, J=8 Hz), 7.85-7.95 (5H, m), 8.02 (1H, s), 8.5-8.6 (2H, m), 10.02 (1H, s)
(15) 2-[3-((E)-2-Benzoylvinyl)phenylamino]-3-nitropyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.10 (1H, dd, J=5 Hz, 8 Hz), 7.5-7.95 (7H, m), 8.03 (1H, d, J=16 Hz), 8.15-8.3 (3H, m), 8.6-8.7 (2H, m), 10.12 (1H, s)
(16) 2-[3-((E)-2-Cyanovinyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 5.93 (1H, d, J=16 Hz), 6.91 (1H, dd, J=5 Hz, 8 Hz), 7.35-7.5 (2H, m), 7.67 (1H, dd, J=1.5 Hz, 8 Hz), 7.91 (1H, t, J=1.5 Hz), 8.45-8.6 (2H, m), 10.18 (1H, s)
(17) 2-[3-((E)-2-Methoxycarbonylvinyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 3.82 (3H, s), 6.48 (1H, d, J=16 Hz), 6.89 (1H, dd, J=5 Hz, 8 Hz), 7.33 (1H, d, J=8 Hz), 7.41 (1H, t, J=8 Hz), 7.63 (1H, d, J=8 Hz), 7.72 (1H, d, J=16 Hz), 8.5-8.6 (2H, m), 10.16 (1H, s)
A mixture of 3-amino-2-chloropyridine (2.57 g) and 3-nitroaniline (2.76 g) was heated at 200xc2x0 C. for 1 hour. The mixture was cooled and partitioned between aqueous sodium bicarbonate solution and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography (chloroform-methanol, 40:1) to afford 3-amino-2-(3-nitrophenylamino)pyridine (141 mg) as an orange solid.
NMR (DMSO-d6, 200 MHz, xcex4): 5.18 (2H, s), 6.74 (1H, dd, J=5 Hz, 8 Hz), 6.99 (1H, dd, J=1.5 Hz, 8 Hz), 7.45-7.7 (3H, m), 8.02 (1H, m), 8.33 (1H, s), 8.66 (1H, t, J=1.5 Hz)
A mixture of 3-nitro-2-((E)-3-styrylphenylamino)pyridine (1.03 g) and 10% palladium on carbon (0.3 g) in methanol (20 ml) and 1,4-dioxane (20 ml) was stirred under hydrogen (3 atm) at room temperature for 1.5 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 3-amino-2-(3-phenethylphenylamino)pyridine (835 mg).
NMR (DMSO-d6, 300 MHz, xcex4): 2.8-2.95 (4H, m), 5.05 (2H, s), 6.61 (1H, dd, J=5 Hz, 8 Hz), 6.72 (1H, d, J=8 Hz), 6.89 (1H, d, J=8 Hz), 7.1-7.35 (6H, m), 7.43 (1H, s), 7.50 (1H, d, J=5 Hz), 7.55 (1H, dd, J=1.5 Hz, 8 Hz), 7.67 (1H, s)
The following compounds were obtained according to similar manners to those of Preparations 3 and 31.
(1) 2-(3-Acetamidophenylamino)-3-amino-6-ethoxypyridine
NMR (DMSO-d6, xcex4): 1.35 (3H, t, J=7 Hz), 2.02 (3H, s), 4.35 (2H, q, J=7 Hz), 6.29 (1H, d, J=7 Hz), 6.82 (1H, m), 6.90 (1H, d, J=7 Hz), 7.05 (1H, dd, J=8 Hz, 8 Hz), 7.20 (1H, m), 7.75 (1H, s), 8.35 (1H, s), 9.71 (1H, s)
(2) 3-Amino-2-[3-[2-(2-naphthyl)ethyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 2.9-3.1 (4H, m), 5.07 (2H, s), 6.61 (1H, dd, J=5 Hz, 8 Hz), 6.76 (1H, d, J=8 Hz), 6.89 (1H, dd, J=1.5 Hz, 8 Hz), 7.12 (1H, t, J=8 Hz), 7.4-7.6 (6H, m), 7.68 (1H, s), 7.75 (1H, s), 7.8-7.9 (3H, m)
A mixture of 2-(3-chlorophenylamino)-3-nitropyridine (394 mg), hydrochloric acid (35% 1.3 ml) and iron powder (0.44 g) in ethanol (5 ml) was refluxed for 15 minutes. The mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-(3-chlorophenylamino)pyridine (281 mg).
NMR (DMSO-d6, 200 MHz, xcex4): 5.12 (2H, s), 6.68 (1H, dd, J=5 Hz, 8 Hz), 6.8-7.0 (2H, m), 7.23 (1H, t, J=8 Hz), 7.45-7.6 (2H, m), 7.89 (1H, t, J=2 Hz), 7.96 (1H, s)
The following compounds were obtained according to a similar manner to that of Preparation 33.
(1) 3-Amino-2-(3-cyanophenylamino)pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.13 (2H, s), 6.71 (1H, dd, J=5 Hz, 8 Hz), 6.97 (1H, dd, J=1.5 Hz, 8 Hz), 7.25 (1H, d, J=8 Hz), 7.42 (1H, t, J=8 Hz), 7.57 (1H, dd, J=1.5 Hz, 5 Hz), 7.82 (1H, dd, J=1.5 Hz, 8 Hz), 8.13 (1H, s), 8.18 (1H, t, J=1.5 Hz)
(2) 3-Amino-2-(3-biphenylylamino)pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.09 (2H, s), 6.6-6.7 (1H, m), 6.92 (1H, dt, J=8 Hz, 1.5 Hz), 7.12 (1H, d, J=8 Hz), 7.25-7.4 (2H, m), 7.45-7.6 (3H, m), 7.63 (2H, d, J=8 Hz), 7.69 (1H, d, J=8 Hz), 7.83 (1H, s), 7.89 (1H, s)
(3) 3-Amino-2-[3-(2-aminothiazol-4-yl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.08 (2H, s), 6.61 (1H, dd, J=5 Hz, 8 Hz), 6.8-6.9 (2H, m), 6.98 (2H, s), 7.15-7.3 (2H, m), 7.49 (1H, m), 7.65 (1H, d, J=8 Hz), 7.76 (1H, s), 7.91 (1H, s)
(4) 3-Amino-2-[3-[2-(pyridin-3-yl)thiazol-4-yl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.12 (2H, s), 6.65 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, d, J=8 Hz), 7.33 (1H, t, J=8 Hz), 7.45-7.6 (3H, m), 7.82 (1H, dd, J=1.5 Hz, 8 Hz), 7.89 (1H, s), 8.14 (1H, s), 8.22 (1H, s), 8.38 (1H, m), 8.69 (1H, d, J=5 Hz), 9.22 (1H, d, J=1.5 Hz)
(5) 3-Amino-2-[3-(imidazol-4-yl)phenylamino]pyridine
NMR (DMSO-d6, 5, 300 MHz, xcex4): 5.07 (2H, s), 6.61 (1H, dd, J=5 Hz, 8 Hz), 6.90 (1H, d, J=8 Hz), 7.15-7.25 (2H, m), 7.4-7.8 (5H, m), 7.94 (1H, s), 12.18 (1H, br s)
(6) 3-Amino-2-[3-(4-methoxybenzoyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 3.87 (3H, s), 5.09 (2H, s), 6.65 (1H, dd, J=5 Hz, 8 Hz), 6.91 (1H, d, J=8 Hz), 7.05-7.2 (3H, m), 7.38 (1H, t, J=8 Hz), 7.49 (1H, m), 7.80 (2H, dt, J=8 Hz, 1.5 Hz), 7.9-8.05 (3H, m)
(7) 3-Amino-2-[3-(3-indolizinylcarbonyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.60-6.75 (2H, m), 6.94 (1H, d, J=8 Hz), 7.11 (1H, m), 7.22 (1H, d, J=8 Hz), 7.25-7.45 (2H, m), 7.5-7.55 (2H, m), 7.75-7.85 (2H, m), 8.00 (1H, s), 8.08 (1H, s), 9.86 (1H, d, J=7 Hz)
(8) 3-Amino-2-((E)-3-styrylphenylamino)pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.07 (2H, s), 6.63 (1H, dd, J=5 Hz, 8 Hz), 6.90 (1H, d, J=8 Hz), 7.05-7.4 (7H, m), 7.5-7.65 (4H, m), 7.78 (2H, d, J=8 Hz)
(9) 3-Amino-2-[3-[(E)-2-(2-naphthyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, d, J=8 Hz), 7.17 (1H, d, J=8 Hz), 7.2-7.65 (7H, m), 7.81 (1H, s), 7.85-8.0 (5H, m), 8.02 (1H, s)
(10) 3-Amino-2-[3-((E)-2-benzoylvinyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.94 (1H, dd, J=1.5 Hz, 8 Hz), 7.34 (1H, t, J=8 Hz), 7.42 (1H, d, J=8 Hz), 7.5-7.9 (8H, m), 7.98 (1H, s), 8.12 (2H, dd, J=1.5 Hz, 8 Hz)
(11) 3-Amino-2-[3-((E)-2-cyanovinyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.09 (2H, s), 6.32 (1H, d, J=16 Hz), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, dd, J=1.5 Hz, 8 Hz), 7.17 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz), 7.5-7.95 (5H, m)
(12) 3-Amino-2-[3-((E)-2-methoxycarbonylvinyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 3.73 (3H, s), 5.08 (2H, s), 6.49 (1H, d, J=16 Hz), 6.66 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, d, J=8 Hz), 7.15-7.35 (2H, m), 7.5-7.75 (3H, m), 7.85 (1H, s), 7.90 (1H, s)
(13) 3-Amino-2-[3-(N-methylacetamido)phenylamino]pyridine
NMR (DMSO-d6, 200 MHz, xcex4): 1.83 (3H, s), 3.16 (3H, s), 5.09 (2H, s), 6.65 (1H, dd, J=5 Hz, 8 Hz), 6.77 (1H, d, J=8 Hz), 6.92 (1H, dd, J=1.5 Hz, 8 Hz), 7.28 (1H, t, J=8 Hz), 7.5-7.65 (3H, m), 7.90 (1H, s)
(14) 3-Amino-2-[3-(4-phenylthiazol-2-yl)aminophenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.09 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, m), 7.0-7.55 (6H, m), 7.53 (1H, d, J=5 Hz), 7.73 (1H, s), 7.91 (2H, d, J=8 Hz), 8.19 (1H, s)
(15) 3-Amino-2-[3-(4-methylthiazol-2-yl)aminophenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 2.21 (3H, s), 5.09 (2H, s), 6.39 (1H, s), 6.62 (1H, dd, J=5 Hz, 8 Hz), 6.89 (1H, d, J=8 Hz), 7.05-7.3 (3H, m), 7.49 (1H, d, J=5 Hz), 7.68 (1H, s), 7.89 (1H, s)
(16) 3-Amino-2-[3-(pyrimidin-2-yl)aminophenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.08 (2H, s), 6.60 (1H, dd, J=5 Hz, 8 Hz), 6.79 (1H, d, J=5 Hz), 6.88 (1H, d, J=8 Hz), 7.10 (1H, t, J=8 Hz), 7.22 (1H, m), 7.30 (1H, m), 7.48 (1H, d, J=5 Hz), 7.66 (1H, s), 7.92 (1H, t, J=1.5 Hz), 8.45 (2H, d, J=5 Hz), 9.47 (1H, s)
(17) 3-Amino-2-[3-(pyrimidin-2-yl)oxyphenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.6-6.7 (2H, m), 6.91 (1H, d, J=8 Hz), 7.2-7.3 (2H, m), 7.4-7.55 (2H, m), 7.60 (1H, s), 7.89 (1H, s), 8.65 (2H, d, J=5 Hz)
(18) 3-Amino-2-[3-(4-phenylpyrimidin-2-yl)oxyphenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.63 (1H, dd, J=5 Hz, 8 Hz), 6.72 (1H, d, J=8 Hz), 6.93 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz), 7.45-7.6 (5H, m), 7.69 (1H, s), 7.84 (1H, d, J=5 Hz), 7.91 (1H, s), 8.1-8.2 (2H, m), 8.68 (1H, d, J=5 Hz)
4N Aqueous solution of sodium hydroxide (2 ml) was added to a solution of ethyl 3-(benzoylamino)benzoate (695 mg) in ethanol (5 ml) and 1,4-dioxane (5 ml). After stirred at 50xc2x0 C. for 1 hour, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated to give 3-(benzoylamino)benzoic acid (595 mg) as solid.
NMR (DMSO-d6, 300 MHz, xcex4): 7.45-7.75 (5H, m), 7.99 (2H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.44 (1H, s)
The following compound was obtained according to a similar manner to that of Preparation 35.
3-(Pyrimidin-2-yl)oxybenzoic acid
NMR (DMSO-d6, 300 MHz, xcex4): 7.30 (1H, t, J=5 Hz), 7.48 (1H, d, J=8 Hz), 7.58 (1H, t, J=8 Hz), 7.69 (1H, s), 7.84 (1H, d, J=8 Hz), 8.67 (2H, d, J=5 Hz)
4N Aqueous solution of sodium hydroxide (1 ml) was added to a solution of ethyl 3-[(3-nitropyridin-2-yl)amino]benzoate (322 mg) in ethanol (2 ml) and 1,4-dioxane (2 ml). After stirred at room temperature for 1 hour, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to give 3-[(3-nitropyridin-2-yl)amino]benzoic acid (263 mg) as solid.
NMR (DMSO-d6, 300 MHz, xcex4): 7.03 (1H, dd, J=5 Hz, 8 Hz), 7.49 (1H, t, J=8 Hz), 7.72 (1H, d, J=8 Hz), 7.88 (1H, d, J=8 Hz), 8.26 (1H, s), 8.5-8.6 (2H, m), 10.03 (1H, s)
A mixture of 3-nitrostyrene (4.6 ml), 3-bromopyridine (2.6 ml), palladium(II) acetate (0.20 g), tetrabutylammonium chloride (8.4 g) and sodium bicarbonate (6.3 g) in N,N-dimethylformamide (40 ml) was stirred at 110xc2x0 C. for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isoprbpyl ether to give 3-[(E)-2-(3-nitrophenyl)vinyl]pyridine (5.34 g).
NMR (CDCl3, 300 MHz, xcex4): 7.21 (2H, s), 7.33 (1H, dd, J=5 Hz, 8 Hz), 7.57 (1H, t, J=8 Hz), 7.8-7.9 (2H, m), 8.13 (1H, dd, J=2 Hz, 8 Hz), 8.38 (1H, t, J=2 Hz), 8.55 (1H, d, J=5 Hz), 8.78 (1H, d, J=2 Hz)
The following compound was obtained according to a similar manner to that of Preparation 38.
5-[(E)-2-(3-Nitrophenyl)vinyl]pyrimidine
NMR (DMSO-d6, 300 MHz, xcex4): 7.51 (1H, d, J=16 Hz), 7.7-7.8 (2H, m), 8.09 (1H, d, J=8 Hz), 8.18 (1H, dd, J=2 Hz, 8 Hz), 8.47 (1H, s), 9.10 (3H, m)
A mixture of 1-iodo-3-nitrobenzene (7.47 g), 2-vinylpyridine (4.73 g), palladium(II) acetate (0.20 g), tetrabutylammonium chloride (8.34 g) and sodium bicarbonate (6.3 g) in N,N-dimethylformamide (50 ml) was stirred at 110xc2x0 C. for 5 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[(E)-2-(3-nitrophenyl)vinyl]pyridine (3.37 g).
NMR (CDCl3, 300 MHz, xcex4): 7.15-7.3 (2H, m), 7.41 (1H, d, J=8 Hz), 7.54 (1H, t, J=8 Hz), 7.65-7.75 (2H, m), 8.13 (1H, dd, J=2 Hz, 8 Hz), 8.43 (1H, s), 8.64 (1H, d, J=5 Hz)
To a solution of 2-bromonaphthalene (5.0 g) and tetrakis(triphenylphosphine)palladium(0) (0.56 g) in toluene (50 ml) was added a solution of dihydroxy(3-nitrophenyl)borane (4.44 g) in methanol and 2M sodium carbonate solution in water (12 ml). The resulting mixture was stirred at 80xc2x0 C. for 4 hours and extracted with ethyl acetate. After evaporation of the solvent, the crude residue was crystallized from hexane to give 3-(2-naphthyl)-1-nitrobenzene (5.4 g).
NMR (CDCl3, xcex4): 7.54 (2H, m), 7.65 (1H, t, J=8 Hz), 7.75 (1H, d, J=8 Hz), 7.91 (2H, m), 7.98 (1H, d, J=8 Hz), 8.05 (1H, dd, J=9 Hz, 2 Hz), 8.11 (1H, s), 8.23 (1H, dd, J=8 Hz, 2 Hz), 8.59 (1H, s)
To a suspension of sodium hydride (60% in oil, 0.75 g) in N,N-dimethylformamide (20 ml) was added a solution of diethyl 3-nitrobenzylphosphonate (4.40 g) in N,N-dimethylformamide (20 ml). The mixture was stirred at room temperature for 15 minutes, then a solution of 4-quinolinecarbaldehyde (2.81 g) in N,N-dimethylformamide (20 ml) was added thereto. After stirring at 50xc2x0 C. fbr 30 minutes, the mixture was poured into aqueous sodium bicarbonate, and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (chloroform-methanol (50:1)) to give 4-[(E)-2-(3-nitrochenyl)vinyl]quinoline (1.57 g) as a solid.
NMR (DMSO-d6, 300 MHz, xcex4): 7.65-7.85 (4H, m), 7.89 (1H, d, J=5 Hz), 8.07 (1H, d, J=8 Hz), 8.21 (1H, dd, J=2 Hz, 8 Hz), 8.3-8.4 (2H, m), 8.62 (1H, d, J=8 Hz), 8.70 (1H, t, J=2 Hz), 8.94 (1H, d, J=5 Hz)
The following compound was obtained according to a similar manner to that of Preparation 42.
2-](E)-2-(3-Nitrophenyl)vinyl]quinoline
NMR (DMSO-d6, 300 MHz, xcex4): 7.60 (1H, t, J=8 Hz), 7.65-7.85 (3H, m), 7.9-8.05 (4H, m), 8.15-8.3 (2H, m), 8.41 (1H, d, J=8 Hz), 8.57 (1H, t, J=2 Hz)
A mixture of 3-[(E)-2-(3-nitrophenyl)vinyl]pyridine (3.64 g), iron powder (3.6 g) and hydrochloric acid (35%, 11 ml) in ethanol (30 ml) was stirred at 80xc2x0 C. for 4 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-[(E)-2-(3-aminophenyl)vinyl]pyridine (1.25 g).
NMR (DMSO-d6, 300 MHz, xcex4): 5.12 (2H, s), 6.52 (1H, dd, J=2 Hz, 8 Hz), 6.75-6.85 (2H, m), 7.0-7.15 (2H, m), 7.23 (1H, d, J=16 Hz), 7.39 (1H, m), 8.02 (1H, m), 8.45 (1H, d, J=5 Hz), 8.75 (1H, d, J=2 Hz)
A mixture of 3-(2-naphthyl)-1-nitrobenzene (5.4 g), iron (3.63 g) and acetic acid (13.0 g) in ethanol (50 ml) was stirred under reflux for 3 hours. The reaction mixture was diluted with chloroform, filtered and treated with saturated sodium bicarbonate solution. The chloroform layer was separated, dried, evaporated and chromatographed on silica gel to give 3-(2-naphthyl)aniline (5.2 g).
NMR (CDCl3, xcex4): 3.75 (2H, br s), 6.70 (1H, dd, J=8 Hz, 2 Hz), 7.03 (1H, s), 7.12 (1H, d, J=8 Hz), 7.27 (1H, dd, J=8 Hz, 8 Hz), 7.47 (2H, m), 7.70 (1H, dd, J=8 Hz, 2 Hz), 7.87 (3H, m), 8.01 (1H, s)
The following compounds were obtained according to a similar manner into that of Preparation 3, 21, 23, 44 or 45.
(1) 2-[(E)-2-(3-Aminophenyl)vinyl]pyridine NMR (DMSO-d6, 300 MHz, xcex4): 5.12 (2H, s), 6.53 (1H, dd, J=2 Hz, 8 Hz), 6.75-6.85 (2H, m), 7.0-7.15 (2H, m), 7.23 (1H, dd, J=5 Hz, 8 Hz), 7.45-7.6 (2H, m), 7.78 (1H, t, J=8 Hz), 8.56 (1H, d, J=5 Hz)
(2) 5-[(E)-2-(3-Aminophenyl)vinyl]pyrimidine
NMR (DMSO-d6, 300 MHz, xcex4): 5.17 (2H, s), 6.55 (1H, dd, J=2 Hz, 8 Hz), 6.79 (2H, m), 7.0-7.1 (2H, m), 7.39 (1H, d, J=16 Hz), 9.03 (3H, m)
(3) 4-[(E)-2-(3-Aminophenyl)vinyl]quinoline
NMR (DMSO-d6, 300 MHz, xcex4): 5.15 (2H, s), 6.60 (1H, dd, J=2 Hz, 8 Hz), 6.95-7.05 (2H, m), 7.11 (1H, t, J=8 Hz), 7.45 (1H, d, J=16 Hz), 7.67 (1H, t, J=8 Hz), 7.75-7.95 (3H, m), 8.05 (1H, d,, J=8 Hz), 8.44 (1H, d, J=8 Hz), 8.88 (1H, d, J=5 Hz)
(4) 2-[(E)-2-(3-Aminophenyl)vinyl]quinoline
NMR (DMSO-d6, 300 MHz, xcex4): 5.18 (2H, s), 6.59 (1H, d, J=8 Hz), 6.85-6.95 (2H, m), 7.10 (1H, t, J=8 Hz), 7.31 (1H, d, J=16 Hz), 7.56 (1H, t, J=8 Hz), 7.65-7.8 (2H, m), 7.85-8.0 (3H, m), 8.33 (1H, d, J=8 Hz)
(5) 3-(3-Biphenylyl)aniline
NMR (CDCl3, xcex4): 3.74 (2H, s), 6.69 (1H, dd, J=8 Hz, 2 Hz), 6.95 (1H, t, J=2 Hz), 7.02 (1H, d, J=8 Hz), 7.24 (1H, m), 7.35 (1H, m), 7.4-7.6 (5H, m), 7.64 (2H, m), 7.79 (1H, s)
A mixture of 2-chloro-3-nitropyridine (1.15 g), 3-[(E)-2-(3-aminophenyl)vinyl]pyridine (1.23 g) and potassium carbonate (1.1 g) in 1,4-dioxane (15 ml) was stirred under reflux for 22 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel column (2% methanol in chloroform) to give 3-nitro-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (510 mg) as an orange solid.
NMR (DMSO-d6, 300 MHz, xcex4): 7.02 (1H, m), 7.3-7.5 (5H, m), 7.65 (1H, m), 7.89 (1H, s), 8.08 (1H, d, J=8 Hz), 8.48 (1H, d, J=5 Hz), 8.5-8.6 (2H, m), 8.80 (1H, d, J=2 Hz)
A mixture of 3-(2-naphthyl)aniline (5.0 g), 2-chloro-3-nitropyridine (3.62 g) and potassium carbonate (6.31 g) in dioxane (50 ml) was stirred under reflux for 6 days. The reaction mixture was extracted with chloroform and evaporated. Crude residue was chromatographed on silica gel to give 2-[3-(2-naphthyl)phenylamino]-3-nitropyridine as an orange crystal (5.23 g).
NMR (DMSO-d6, xcex4): 7.02 (1H, dd, J=8 Hz, 5 Hz), 7.55 (4H, m), 7.75 (1H, m), 7.85-8.1 (5H, m), 8.26 (1H, s), 8.55 (2H, m)
A mixture of 2-chloro-3-nitropyridine (8.5 g), 3-iodoaniline (12.5 g) and potassium carbonate (9.0 g) in 1,4-dioxane (100 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-(3-iodophenylamino)-3-nitropyridine (3.88 g) as an orange solid.
NMR (CDCl3, 300 MHz, xcex4): 6.89 (1H, dd, J=5 Hz, 8 Hz), 7.11 (1H, t, J=8 Hz), 7.50 (1H, d, J=8 Hz), 7.60 (1H, dd, J=2, 8 Hz), 8.12 (1H, s), 8.45-8.6 (2H, m)
The following compounds were obtained according to a similar manner to that of Preparation 1, 5, 27, 28, 47, 48 or 49.
(1) 3-Nitro-2-[3-[(E)-2-(2-pyridyl)vinyl]phenylamino]pyridine
NMR (CDCl3, 300 MHz, xcex4): 6.87 (1H, dd, J=2 Hz, 8 Hz), 7.4-7.8 (7H, m), 7.98 (1H, s), 8.05-8.2 (2H, m), 8.5-8.6 (2H, m)
(2) 3-Nitro-2-[3-[(E)-2-(5-pyrimidinyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.02 (1H, dd, J=5 Hz, 8 Hz), 7.28 (1H, d, J=16 GHz), 7.49-7.5 (2H, m), 7.58 (1H, d, J=16 Hz), 7.68 (1H, m), 7.90 (1H, s), 8.5-8.6 (2H, m), 9.0-9.1 (3H, m)
(3) 3-Nitro-2-[3-[(E)-2-(4-quinolyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.02 (1H, dd, J=5, 8 Hz), 7.47 (1H, t, J=8 Hz), 7.55-7.85 (6H, m), 7.89 (1H, d, J=5 Hz), 8.05-8.2 (6H, m), 8.5-8.6 (3H, m), 8.90 (1H, d, J=5 Hz)
(4) 3-Nitro-2-[3-[(E)-2-(2-quinolyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.03 (1H, dd, J=5, 8 Hz), 7.4-7.6 (4H, m), 7.7-8.05 (7H, m), 8.37 (1H, d, J=8 Hz), 8.55-8.6 (2H, m)
(5) 2-[3-(2-Cyanopyrrol-1-yl)phenylamino]-3-nitropyridine
NMR (DMSO-d6, xcex4): 6.46 (1H, m), 7.06 (1H, m), 7.25 (1H, m), 7.31 (1H, m), 7.56 (1H, m), 7.78 (1H, m), 8.03 (1H, m), 8.56 (2H, m)
(6) 2-[3-(Benzothiazol-2-yl)phenylamino]-3-nitropyridine
NMR (DMSO-d6, xcex4): 7.06 (1H, dd, J=8 Hz, 4 Hz), 7.50 (1H, dd, J=8 Hz, 8 Hz), 7.57 (2H, dd, J=8 Hz, 8 Hz), 7.88 (2H, m), 8.09 (1H, d, J=8 Hz), 8.18 (1H, d, J=8 Hz), 8.46 (1H, m), 8.57 (2H, m)
(7) 2-(3-Benzoylphenylamino)-3-nitropyridine
NMR (CDCl3, xcex4): 6.88 (1H, dd, J=8 Hz, 5 Hz), 7.51 (3H, m), 7.60 (2H, m), 7.88 (3H, m), 8.14 (1H, m), 8.49 (1H, dd, J=5 Hz, 2 Hz), 8.55 (1H, dd, J=8 Hz, 2 Hz)
(8) 2-(3-Trifluoromethylphenylamino)-3-nitropyridine
NMR (DMSO-d6, xcex4): 7.05 (1H, dd, J=8 Hz, 4 Hz), 7.45 (1H, d, J=8 Hz), 7.60 (1H, dd, J=8 Hz, 8 Hz), 7.92 (1H, d, J=8 Hz), 8.12 (1H, s), 8.53 (2H, m)
(9) 2-[3-(Indol-1-yl)phenylamino]-3-nitropyridine
NMR (CDCl3, xcex4): 6.70 (1H, d, J=3 Hz), 6.89 (1H, dd, J=8 Hz, 4 Hz), 7.17 (1H, m), 7.21 (1H, m), 7.30 (1H, m), 7.39 (1H, d, J=3 Hz), 7.50 (2H, m), 7.72 (2H, m), 8.10 (1H, m), 8.50 (1H, m), 8.55 (1H, m)
(10) 2-(3-Carboxyphenylamino)-3-nitropyridine
NMR (DMSO-d6, xcex4): 7.03 (1H, dd, J=8 Hz, 5 Hz), 7.50 (1H, dd, J=8 Hz, 8 Hz), 7.71 (1H, m), 7.88 (1H, m), 8.25 (1H, m), 8.55 (2H, m)
(11) 2-[(5-Acetamido-2-fluorophenyl)amino]-3-nitropyridine
NMR (CDCl3, xcex4): 2.15 (3H, s), 6.92 (1H, dd, J=8 Hz, 5 Hz), 7.11 (1H, dd, J=8 Hz, 8 Hz), 7.35 (1H, m), 8.55 (3H, m)
(12) 2-[3-(1-Naphthyl)phenylamino]-3-nitropyridine
NMR (CDCl3, xcex4): 6.83 (1H, dd, J=8 Hz, 5 Hz), 7.31 (1H, d, J=7 Hz), 7.4-7.55 (5H, m), 7.74 (1H, dd, J=8 Hz, 2 Hz), 7.79 (1H, m), 7.90 (2H, m), 8.00 (1H, d, J=8 Hz), 8.47 (1H, m), 8.53 (1H, d, J=8 Hz)
(13) 2-[3-(3-Biphenylyl)phenylamino]-3-nitropyridine
NMR (CDCl3, xcex4): 6.86 (1H, dd, J=8 Hz, 6 Hz), 7.39 (1H, m), 7.4-7.7 (11H, m), 7.83 (1H, s), 7.89 (1H, s), 8.50 (2H, m)
A mixture of 2-(3-iodophenylamino)-3-nitropyridine (3.86 g), 4-vinylpyridine (1.78 g), palladium(II) acetate (80 mg), tetrabutylammonium chloride (3.14 g) and sodium bicarbonate (2.4 g) in N,N-dimethylformamide (20 ml) was stirred at 110xc2x0 C. for 22 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (chloroform-methanol (50:1)) to give 3-nitro-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (1.41 g) as an orange solid.
NMR (CDCl3, 300 MHz, xcex4): 6.88 (1H, dd, J=5 Hz, 8 Hz), 7.07 (1H, d, J=16 Hz), 7.3-7.5 (5H, m), 7.62 (1H, d, J=8 Hz), 7.85 (1H, s), 8.5-8.65 (4H, m)
A mixture of 3-nitro-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (493 mg), iron powder (0.35 g) and hydrochloric acid (35%, 1 ml) in methanol (5 ml) was stirred under reflux for 4 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (291 mg).
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.66 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, d, J=8 Hz), 7.1-7.45 (5H, m), 7.54 (1H, d, J=5 Hz), 7.62 (1H, d, J=8 Hz), 7.80 (2H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz), 8.47 (1H, d, J=5 Hz), 8.79 (1H, d, J=2 Hz)
A mixture of 3-nitro-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (1.38 g), iron powder (1.0 g) and hydrochloric acid (35%, 3.0 ml) in ethanol (10 ml) was stirred at 80xc2x0 C. for 2 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (8% methanol in chloroform) to give 3-amino-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (1.14 g) as powder.
NMR (DMSO-d6, 300 MHz, xcex4): 5.09 (2H, s), 6.65 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, d, J=8 Hz), 7.1-7.2 (2H, m), 7.28 (1H, t, J=8 Hz), 7.45-7.7 (5H, m), 7.82 (1H, s), 7.88 (1H, s), 8.54 (2H, d, J=5 Hz)
A mixture of 2-[3-(2-naphthyl)phenylamino]-3-nitropyridine (3.0 g), iron (2.46 g) and acetic acid (5.28 g) in ethanol (14 ml) was stirred under reflux for 6 hours. The reaction mixture was diluted with chloroform, filtered and treated with saturated sodium bicarbonate solution. The chloroform layer was separated, dried, evaporated and chromatographed on silica gel to give 2-[3-(2-naphthyl)phenylamino]-3-aminopyridine (1.2 g, 43.9%).
NMR (CDCl3, xcex4): 5.10 (2H, s), 6.65 (1H, dd, J=8 Hz, 6 Hz), 6.94 (1H, dd, J=8 Hz, 2 Hz), 7.28 (1H, m), 7.37 (1H, dd, J=8 Hz, 8 Hz), 7.53 (3H, m), 7.77 (1H, m), 7.81 (1H, d, J=8 Hz), 7.90 (1H, s), 7.95 (1H, m), 8.00 (3H, m), 8.16 (1H, s)
The following compounds were obtained according to a similar manner to that of Preparation 3, 31, 33, 52, 53 or 54.
(1) 3-Amino-2-[3-[(E)-2-(2-pyridyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.66 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, d, J=8 Hz), 7.1-7.3 (4H, m), 7.55-7.7 (4H, m), 7.75-7.85 (2H, m), 7.90 (1H, s), 8.59 (1H, d, J=5 Hz)
(2) 3-Amino-2-[3-[(E)-2-(5-pyrimidinyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.66 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, d, J=8 Hz), 7.1-7.2 (2H, m), 7.29 (1H, t, J=8 Hz), 7.45-7.55 (2H, m), 7.62 (1H, d, J=8 Hz), 7.83 (2H, d, J=8 Hz), 9.0-9.1 (1H, m)
(3) 3-Amino-2-[3-[(E)-2-(2-quinolyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.68 (1H, dd, J=5 Hz, 8 Hz), 6.95 (1H, d, J=8 Hz), 7.2-7.45 (3H, m), 7.5-7.6 (2H, m), 7.65 (1H, d, J=8 Hz), 7.7-8.05 (7H, m), 8.36 (1H, d, J=8 Hz)
(4) 3-Amino-2-[3-[(E)-2-(4-quinolyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.94 (1H, d, J=8 Hz), 7.3-7.45 (2H, m), 7.5-7.6 (2H, m), 7.65-8.1 (8H, m), 8.48 (1H, d, J=8 Hz), 8.89 (1H, d, J=5 Hz)
(5) 2-[3-(Benzothiazol-2-yl)phenylamino]-3-aminopyridine
NMR (DMSO-d6, xcex4): 5.15 (2H, s), 6.70 (1H, dd, J=8 Hz, 5 Hz), 6.97 (1H, dd, J=8 Hz, 2 Hz), 7.4-7.5 (2H, m), 7.56 (3H, m), 7.96 (1H, dd, J=8 Hz, 2 Hz), 8.08 (2H, m), 8.16 (1H, d, J=8 Hz), 8.40 (1H, m)
(6) 2-[3-(3-Acetylindol-1-yl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 2.57 (3H, s), 3.49 (2H, br s), 6.49 (1H, s), 6.80 (1H, dd, J=8 Hz, 5 Hz), 7.05 (2H, m), 7.30 (4H, m), 7.45 (1H, dd, J=9 Hz, 8 Hz), 7.61 (1H, m), 7.68 (1H, m), 7.87 (1H, m), 7.95 (1H, s), 8.44 (1H, m)
(7) 2-[3-(2-Cyanopyrrol-1-yl)phenylamino]-3-aminopyridine
NMR (DMSO-d6, xcex4): 5.13 (2H, s), 6.43 (1H, m), 6.67 (1H, m), 6.95 (2H, m), 7.20 (1H, m), 7.40 (1H, dd, J=8 Hz, 8 Hz), 7.48 (1H, m), 7.52 (1H, m), 7.66 (1H, m), 7.98 (1H, m), 8.10 (1H, s)
(8) 2-(3-Benzoylphenylamino)-3-aminopyridine
NMR (CDCl3, xcex4): 3.45 (2H, br s), 6.37 (1H, s), 6.79 (1H, dd, J=8 Hz, 5 Hz), 7.02 (1H, dd, J=8 Hz, 2 Hz), 7.38 (2H, m), 7.49 (2H, m), 7.60 (2H, m), 7.69 (1H, m), 7.84 (3H, m)
(9) 2-(3-Trifluoromethylphenylamino)-3-aminopyridine
NMR (CDCl3, xcex4): 3.41 (2H, br s), 6.38 (1H, br s), 6.82 (1H, dd, J=8 Hz, 5 Hz), 7.05 (1H, dd, J=8 Hz, 2 Hz), 7.18 (1H, d, J=8 Hz), 7.37 (1H, dd, J=8 Hz, 8 Hz), 7.49 (1H, d, J=8 Hz), 7.55 (1H, br s), 7.85 (1H, dd, J=5 Hz, 2 Hz)
(10) 2-(3-Methoxycarbonylphenylamino)-3-aminopyridine
NMR (DMSO-d6, xcex4): 3.83 (3H, s), 5.30 (2H, br s), 6.68 (1H, dd, J=8 Hz, 6 Hz), 6.95 (1H, d, J=8 Hz), 7.37 (1H, dd, J=8 Hz, 8 Hz), 7.44 (1H, d, J=8 Hz), 7.51 (1H, d, J=6 Hz), 7.99 (1H, d, J=8 Hz), 8.09 (1H, s), 8.18 (1H, s)
(11) 2-[(5-Acetamido-2-fluorophenyl)amino]-3-aminopyridine
NMR (CDCl3, xcex4): 2.09 (3H, s), 6.80 (1H, dd, J=8 Hz, 5 Hz), 7.00 (1H, dd, J=8 Hz, 8 Hz), 7.05 (1H, dd, J=8 Hz, 2 Hz), 7.22 (1H, m), 7.72 (2H, m)
(12) 2-[3-(1-Indolyl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 3.43 (2H, br s), 6.35 (1H, s), 6.67 (1H, m), 6.80 (1H, m), 7.05 (2H, m), 7.20 (3H, m), 7.38 (2H, m), 7.55 (1H, s), 7.69 (1H, dd, J=8 Hz, 8 Hz), 7.83 (1H, d, J=3 Hz)
(13) 2-[3-(1-Naphthyl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 3.40 (2H, br s), 6.29 (1H, s), 6.75 (1H, dd, J=8 Hz, 6 Hz), 6.97 (1H, d, J=8 Hz), 7.08 (1H, m), 7.30 (1H, s), 7.35-7.55 (6H, m), 7.85 (3H, m), 8.01 (1H, d, J=8 Hz)
(14) 2-[3-(3-Biphenylyl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 3.45 (2H, br s), 6.30 (1H, s), 6.80 (1H, dd, J=8 Hz, 6 Hz), 7.03 (1H, d, J=8 Hz), 7.2-7.7 (12H, m), 7.80 (1H, m), 7.87 (1H, m)
A mixture of 2-[3-(indol-1-yl)phenylamino]-3-nitropyridine (1.0 g), acetic anhydride (0.46 g), and aluminum chloride (1.21 g) in dry methylene chloride (10 ml) was stirred at room temperature for 3 hours. The reaction mixture was treated with 1N sodium hydroxide solution and precipitated brown crystals were collected, washed with water and dried to give 2-[3-(3-acetylindol-1-yl)phenylamino]-3-nitropyridine (1.17 g).
NMR (DMSO-d6, xcex4): 2.54 (3H, s), 7.06 (1H, dd, J=8 Hz, 6 Hz), 7.33 (2H, m), 7.45 (1H, m), 7.63 (1H, dd, J=8 Hz, 8 Hz), 7.73 (1H, m), 7.78 (1H, m), 8.09 (1H, m), 8.32 (1H, m), 8.57 (1H, m), 8.66 (1H, s)
The following compounds were obtained according to a similar manner to that of Preparation 41.
(1) 3-(1-Naphthyl)-1-nitrobenzene
NMR (CDCl3, xcex4): 7.4-7.6 (4H, m), 7.68 (1H, t, J=8 Hz), 7.77 (1H, d, J=8 Hz), 7.83 (1H, dd, J=8 Hz, 2 Hz), 7.93 (2H, m), 8.30 (1H, dd, J=8 Hz, 2 Hz), 8.39 (1H, m)
(2) 3-(3-Biphenylyl)-1-nitrobenzene
NMR (CDCl3, xcex4): 7.35-7.75 (9H, m), 7.82 (1H, s), 7.98 (1H, d, J=8 Hz), 8.23 (1H, dd, J=8 Hz, 2 Hz), 8.50 (1H, m)
To a solution of 2-methyl-4-(3-aminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (7.4 g) and triethylamine (5.72 ml) in dioxane was added 3,5-dichlorobenzoyl chloride (6.14 g) in dropwise. The mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched by water and extracted with ethyl acetate (100 ml). The crude product was purified by chromatography to obtain 2-methyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.4 g).
NMR (CDCl3, 300 MHz, xcex4): 9.09 (1H, br s), 8.38 (1H, m), 8.19 (1H, d, J=7 Hz), 7.80 (1H, s), 7.68 (2H, s), 7.52 (1H, d, J=6 Hz), 7.39 (1H, s), 7.35-7.23 (2H, m), 6.54 (1H, d, J=6 Hz), 2.73 (3H, s)
A mixture of 3-nitrophenylhydrazine hydrochloride (8.77 g) and 1,3,5-triazine (2.50 g) in ethanol (40 ml) was stirred under reflux for 4 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 3:7) to give 1-(3-nitrophenyl)-1H-1,2,4-triazole (2.89 g) as a solid.
NMR (CDCl3, 300 MHz, xcex4): 7.74 (1H, t, J=8 Hz), 8.10 (1H, dt, J=8 Hz, 2 Hz), 8.18 (1H, s), 8.28 (1H, dt, J=8 Hz, 2 Hz)., 8.60 (1H, t, J=2 Hz), 8.70 (1H, s)
To a solution of morpholine (5.0 ml) in dichloromethane (50 ml) was added 3-nitrobenzoyl chloride (5.05 g). The mixture was stirred at room temperature for 15 minutes, then poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give 4-(3-nitrophenylcarbonyl)morpholine (6.46 g).
NMR (CDCl3, 300 MHz, xcex4): 3.3-4.0 (8H, m), 7.65 (1H, t, J=8 Hz), 7.78 (1H, dt, J=8 Hz, 2 Hz), 8.30 (2H, m)
To a mixture of 4-bromopyridine hydrochloride (5.25 g) and tetrakis(triphenylphosphine)palladium(0) (0.93 g) in toluene (50 ml) was added 3M aqueous solution of sodium bicarbonate (27 ml) and a solution of dihydroxy(3-nitrophenyl)borane (5.0 g) in methanol (12 ml). The mixture was stirred at 80xc2x0 C. for 1 hour and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1%-2% methanol in chloroform) to give 4-(3-nitrophenyl)pyridine (3.46 g).
NMR (CDCl3, 300 MHz, xcex4): 7.57 (2H, dd, J=2 Hz, 5 Hz), 7.70 (1H, t, J=8 Hz), 7.98 (1H, dt, J=8 Hz, 2 Hz), 8.32 (1H, m), 8.51 (1H, t, J=2 Hz), 8.76 (2H, d, J=5 Hz)
To a mixture of 2-bromopyridine (1.91 ml) and tetrakis(triphenylphosphine)palladium(0) (0.46 g) in 1,2-dimethoxyethane (40 ml) was added 2M aqueous solution of sodium bicarbonate (20 ml) and a solution of dihydroxy(3-nitrophenyl)borane (3.67 g) in methanol (10 ml). The mixture was stirred at 80xc2x0 C. for 2.5 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:1)) to give 2-(3-nitrophenyl)pyridine (1.35 g).
NMR (CDCl3, 300 MHz, xcex4): 7.32 (1H, m), 7.65 (1H, t, J=8 Hz), 7.83 (2H, m), 8.27 (1H, m), 8.38 (1H, d, J=8 Hz), 8.73 (1H, m), 8.87 (1H, t, J=2 Hz)
To a mixture of 3-bromopyridine (2.6 ml) and tetrakis(triphenylphosphine)palladium(0) (0.93 g) in toluene (50 ml) was added 2M aqueous solution of sodium bicarbonate (27 ml) and a solution of dihydroxy(3-nitrophenyl)borane (5.0 g) in methanol (12 ml). The mixture was stirred at 80xc2x0 C. for 6 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:7)) to give 3-(3-nitrophenyl)pyridine (3.57 g).
NMR (CDCl3, 300 MHz, xcex4): 7.46 (1H, dd, J=5 Hz, 8 Hz), 7.69 (1H, t, J=8 Hz), 7.9-8.0 (2H, m), 8.28 (1H, dt, J=8 Hz, 2 Hz), 8.47 (1H, t, J=2 Hz), 8.70 (1H, dd, J=2 Hz, 5 Hz), 8.90 (1H, d, J=2 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 41, 61, 62 or 63.
(1) 2-(3-Nitrophenyl)thiophene
NMR (CDCl3, 300 MHz, xcex4): 7.13 (1H, dd, J=4 Hz, 5 Hz), 7.39 (1H, dd, J=1 Hz, 5 Hz), 7.45 (1H, dd, J=1 Hz, 4 Hz), 7.55 (1H, t, J=8 Hz), 7.91 (1H, m), 8.12 (1H, dt, J=8 Hz, 2 Hz), 8.47 (1H, t, J=2 Hz)
(2) 2-Chloro-5-(3-nitrophenyl)thiophene
NMR (CDCl3, 300 MHz, xcex4): 6.97 (1H, d, J=4 Hz), 7.21 (1H, d, J=4 Hz), 7.57 (1H, t, J=8 Hz), 7.80 (1H, dt, J=8 Hz, 2 Hz), 8.14 (1H, dt, J=8 Hz, 2 Hz), 8.37 (1H, t, J=2 Hz)
(3) 3-(3-Nitrophenyl)thiophene
NMR (CDCl3, 300 MHz, xcex4): 7.45-7.5 (2H, m), 7.58 (1H, m), 7.92 (1H, dt, J=8 Hz, 2 Hz), 8.14 (1H, dt, J=8 Hz, 2 Hz), 8.45 (1H, t, J=2 Hz)
(4) 1-(2-Fluorophenyl)-3-nitrobenzene
NMR (CDCl3, 300 MHz, xcex4): 7.15-7.3 (2H, m), 7.35-7.55 (2H, m), 7.63 (1H, t, J=8 Hz), 7.90 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 8.43 (1H, s)
(5) Methyl 4-(3-nitrophenyl)benzoate
NMR (CDCl3, 300 MHz, xcex4): 3.98 (3H, s), 7.6-7.75 (3H, m), 7.97 (1H, dt, J=8 Hz, 2 Hz), 8.18 (2H, dt, J=8 Hz, 2 Hz), 8.27 (1H, dt, J=8 Hz, 2 Hz), 8.49 (1H, t, J=2 Hz)
(6) 4-(3-Nitrophenyl)acetanilide
NMR (DMSO-d6, 300 MHz, xcex4): 2.09 (3H, s), 7.8-7.9 (5H, m), 8.1-8.2 (2H, m), 8.40 (1H, s)
(7) 3-(6-Methoxy-2-naphthyl)aniline
NMR (DMSO-d6, xcex4): 3.89 (3H, s), 5.16 (2H, s), 6.56 (1H, m), 6.90 (1H, m), 6.96 (1H, m), 7.12 (1H, d, J=8 Hz), 7.18 (1H, dd, J=8 Hz, 2 Hz), 7.33 (1H, m), 7.69 (1H, m), 7.88 (2H, m), 8.00 (1H, m)
(8) 3-(3-Quinolyl)aniline
NMR (CDCl3, xcex4): 3.85 (2H, s), 6.75 (1H, dd, J=8 Hz, 2 Hz), 7.00 (1H, m), 7.10 (1H, d, J=8 Hz), 7.30 (1H, dd, J=8 Hz, 8 Hz), 7.55 (1H, dd, J=8 Hz, 8 Hz), 7.72 (1H, dd, J=8 Hz, 8 Hz), 7.85 (1H, d, J=8 Hz), 8.12 (1H, d, J=8 Hz), 8.25 (1H, d, J=2 Hz), 9.15 (1H, s)
(9) 3-(3-Cyclopentyloxy-4-methoxyphenyl)aniline
NMR (CDCl3, xcex4): 1.60 (2H, m), 1.8-2.0 (8H, m), 3.71 (2H, s), 3.87 (3H, s), 4.84 (1H, m), 6.64 (1H, m), 6.85 (1H, m), 6.92 (2H, m), 7.09 (2H, m), 7.20 (1H, m)
(10) 3-(3-Methoxycarbonylphenyl)aniline
NMR (CDCl3, xcex4): 3.92 (3H, s), 6.68 (1H, dd, J=8 Hz, 3 Hz), 6.93 (1H, s), 7.00 (1H, dd, J=8 Hz, 2 Hz), 7.24 (1H, dd, J=8 Hz, 3 Hz), 7.47 (1H, dd, J=8 Hz, 8 Hz), 7.73 (1H, dd, J=8 Hz, 2 Hz), 7.99 (1H, dd, J=8 Hz, 2 Hz), 8.24 (1H, dd, J=2 Hz, 2 Hz)
MASS (m/z): 228 (M+1)
(11) Methyl (E)-3-(3-aminophenyl)cinnamate
NMR (CDCl3, xcex4): 3.77 (2H, br s), 3.81 (3H, s), 6.50 (1H, d, J=15 Hz), 6.70 (1H, dd, J=8 Hz, 2 Hz), 6.90 (1H, d, J=2 Hz), 6.98 (1H, d, J=8 Hz), 7.24 (1H, dd, J=8 Hz, 8 Hz), 7.43 (1H, dd, J=8 Hz, 8 Hz), 7.50 (1H, m), 7.58 (1H, m), 7.70 (1H, m), 7.75 (1H, d, J=15 Hz)
(12) 3-(4-Isoquinolyl)aniline
NMR (CDCl3, xcex4): 3.80 (2H, s), 6.80 (2H, m), 6.90 (1H, d, J=8 Hz), 7.30 (1H, dd, J=8 Hz, 8 Hz), 7.63 (2H, m), 8.00 (2H, m), 8.78 (1H, s), 9.23 (1H, s)
(13) 3-(3-Acetamidophenyl)aniline
NMR (DMSO-d6, xcex4): 2.05 (3H, s), 5.17 (2H, s), 6.54 (1H, m), 6.70 (1H, m), 6.80 (1H, m), 7.10 (1H, dd, J=8 Hz, 8 Hz), 7.20 (1H, m), 7.32 (1H, dd, J=8 Hz, 8 Hz), 7.50 (1H, m), 7.82 (1H, m)
MASS (m/z): 227 (M+1)
A mixture of 4-(3-nitrophenyl)acetanilide (4.25 g) and 10% palladium on carbon (0.8 g) in ethanol (50 ml) and 1,4-dioxane (50 ml) was stirred under hydrogen (3 atm) at room temperature for 3 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 4-(3-aminophenyl)acetanilide (3.40 g).
NMR (DMSO-d6, 300 MHz, xcex4): 2.05 (3H, s), 5.11 (2H, s), 6.52 (1H, d, J=8 Hz), 6.74 (1H, d, J=8 Hz), 6.81 (1H, s), 7.07 (1H, t, J=8 Hz), 7.49 (2H, d, J=8 Hz), 7.63 (2H, d, J=8 Hz)
A mixture of methyl 4-(3-nitrophenyl)benzoate (8.37 g), iron powder (7.5 g) and hydrochloric acid (35%, 22 ml) in methanol (60 ml) was stirred under reflux for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give methyl 4-(3-aminophenyl)benzoate (5.33 g).
NMR (DMSO-d6, 300 MHz, xcex4): 3.88 (3H, s), 5.22 (2H, s), 6.62 (1H, dt, J=8 Hz, 2 Hz), 6.84 (1H, dt, J=8 Hz, 2 Hz), 6.90 (1H, t, J=2 Hz), 7.13 (1H, t, J=8 Hz), 7.70 (2H, dt, J=8 Hz, 2 Hz), 8.01 (2H, dt, J=8 Hz, 2 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 3, 21, 23, 44, 45, 65 or 66.
(1) 4-(3-Aminophenylcarbonyl)morpholine
NMR (DMSO-d6, 300 MHz, xcex4): 3.2-3.7 (8H, m), 5.23 (2H, s), 6.47 (1H, dt, J=8 Hz, 2 Hz), 6.54 (1H, t, J=2 Hz), 6.60 (1H, dt, J=8 Hz, 2 Hz), 7.06 (1H, t, J=8 Hz)
(2) 3-(2-Fluorophenyl)aniline
NMR (DMSO-d6, 300 MHz, xcex4): 5.18 (2H, s), 6.5-6.7 (2H, m), 6.72 (1H, m), 7.10 (1H, t, J=8 Hz), 7.2-7.5 (4H, m)
(3) 1-(3-Aminophenyl)-1H-1,2,4-triazole
NMR (DMSO-d6, xcex4): 5.48 (2H, s), 6.59 (1H, m), 6.93 (1H, m), 7.03 (1H, t, J=2 Hz), 7.17 (1H, t, J=8 Hz), 8.18 (1H, s), 9.14 (1H, s)
(4) 3-(3-Aminophenyl)thiophene
NMR (DMSO-d6 300 MHz, xcex4): 5.09 (2H, s), 6.50 (1H, dd, J=2 Hz, 8 Hz), 6.8-6.9 (2H, m), 7.05 (1H, t, J=8 Hz), 7.40 (1H, dd, J=2 Hz, 5 Hz), 7.60 (1H, m), 7.65 (1H, t, J=2 Hz)
(5) 2-(3-Aminophenyl)-5-chlorothiophene
NMR (DMSO-d6, 300 MHz, xcex4): 5.24 (2H, s), 6.53 (1H, dd, J=2 Hz, 5 Hz), 6.7-6.75 (2H, m), 7.0-7.15 (2H, m), 7.21 (1H, d, J=4 Hz)
(6) 2-(3-Aminophenyl)thiophene
NMR (DMSO-d6, 300 MHz, xcex4): 5.20 (2H, s), 6.50 (1H, m), 6.75-6.85 (2H, m), 7.0-7.15 (2H, m), 7.33 (1H, dd, J=1 Hz, 4 Hz), 7.47 (1H, dd, J=1 Hz, 5 Hz)
(7) 4-(3-Aminophenyl)pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.27 (2H, s), 6.67 (1H, dd, J=2 Hz, 8 Hz), 6.85-6.95 (2H, m), 7.15. (1H, t, J=8 Hz), 7.57 (2H, dd, J=2 Hz, 5 Hz), 8.59 (2H, d, J=5 Hz)
(8) 3-(3-Aminophenyl)pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.23 (2H, s), 6.62 (1H, m), 6.8-6.9 (2H, m), 7.13 (1H, t, J=8 Hz), 7.45 (1H, dd, J=5 Hz, 8 Hz), 7.94 (1H, dt, J=8 Hz, 2 Hz), 8.53 (1H, d, J=5 Hz), 8.78 (1H, d, J=2 Hz)
(9) 2-(3-Aminophenyl)pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.19 (2H, s), 6.62 (1H, m), 7.05-7.2 (2H, m), 7.25-7.35 (2H, m), 7.75-7.85 (2H, m), 8.61 (1H, m)
(10) 3-(Benzoylamino)aniline
NMR (DMSO-d6, 300 MHz, xcex4): 5.07 (2H, s), 6.34 (1H, d, J=8 Hz), 6.86 (1H, d, J=8 Hz), 6.97 (1H, t, J=8 Hz), 7.14 (1H, s), 7.5-7.6 (3H, m), 7.95 (2H, d, J=8 Hz), 9.97 (1H, s)
(11) Methyl 1-(3-aminophenyl)indole-5-carboxylate
NMR (CDCl3, xcex4): 3.86 (2H, s), 3.92 (3H, s), 6.70 (2H, m), 6.77 (1H, m), 6.85 (1H, d, J=8 Hz), 7.27 (1H, d, J=8 Hz), 7.35 (1H, d, J=3 Hz), 7.57 (1H, d, J=8 Hz), 7.90 (1H, d, J=8 Hz), 8.42 (1H, s)
(12) 3-(3-Aminophenylcarbamoyl)quinoline
NMR (DMSO-d6, 300 MHz, xcex4): 5.14 (2H, s), 6.37 (1H, d, J=8 Hz), 6.9-7.05 (2H, m), 7.15 (1H, s), 7.72 (1H, t, J=8 Hz), 7.90 (1H, t, J=8 Hz), 8.1-8.2 (2H, m), 8.92 (1H, s), 9.33 (1H, d, J=2 Hz)
(13) 3-[(E)-2-(3,5-Dichlorophenyl)vinyl]aniline
NMR (DMSO-d6, 300 MHz, xcex4): 5.13 (2H, s), 6.53 (1H, d, J=8 Hz), 6.78 (2H, m), 7.0-7.1 (2H, m), 7.31 (1H, d, J=16 Hz), 7.46 (1H, s), 7.69 (2H, s)
(14) 3-Amino-N-(3,5-dichlorophenyl)benzamide
NMR (DMSO-d6, 300 MHz, xcex4): 5.37 (2H, s), 7.0-7.1 (2H, m), 7.17 (1H, t, J=8 Hz), 7.30 (1H, s), 7.89 (1H, d, J=2 Hz)
(15) 3-Amino-N-methyl-N-(3,5-dichlorophenyl)benzamide
NMR (DMSO-d6, 300 MHz, xcex4): 3.32 (3H, s), 5.20 (2H, s), 6.33 (1H, d, J=8 Hz), 6.51 (1H, dd, J=2 Hz, 8 Hz), 6.59 (1H, s), 6.90 (1H, t, J=8 Hz), 7.29 (2H, s), 7.40 (1H, s)
A mixture of 2-chloro-3-nitropyridine (3.20 g), methyl 3,5-diaminobenzoate (3.20 g) and potassium carbonate (4.0 g) in 1,4-dioxane (60 ml) was stirred under reflux for 4 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel column (5% methanol in chloroform) to give 2-(3-amino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.12 g).
NMR (DMSO-d6, 300 MHz, xcex4): 3.81 (3H, s), 5.48 (2H, s), 6.95-7.0 (2H, m), 7.12 (1H, m), 7.39 (1H, s), 8.5-8.55 (2H, m), 9.86 (1H, s)
A mixture of 2-chloro-3-nitropyridine (1.15 g), 2-(3-aminophenyl)pyridine (1.12 g) and potassium carbonate (1.36 g) in diglyme (15 ml) was stirred at 150xc2x0 C. for 3 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 1:1) to give 3-nitro-2-[3-(2-pyridyl)phenylamino]pyridine (1.68 g)
NMR (CDCl3, 300 MHz, xcex4): 6.85 (1H, dd, J=5 Hz, 8 Hz), 7.2-7.3 (1H, m), 7.50 (1H, t, J=8 Hz), 7.75-7.85 (4H, m), 8.23 (2H, m), 8.5-8.6 (1H, m), 8.70 (1H, d, J=5 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 1, 5, 27, 28, 47, 48, 49, 68 or 69.
(1) 2-[3,5-Bis(methoxycarbonyl)phenylamino]-3-nitropyridine
NMR (DMSO-d6, 300 MHz, xcex4): 3.92 (6H, s), 7.09 (1H, dd, J=5 Hz, 8 Hz), 8.22 (1H, m), 8.5-8.6 (4H, m)
(2) 2-[3-(Morpholinocarbonyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 3.5-3.9 (8H, m), 6.90 (1H, dd, J=5 Hz, 8 Hz), 7.10 (1H, dt, J=8 Hz, 2 Hz), 7.44 (1H, t, J=8 Hz), 7.68 (1H, dt, J=8 Hz, 2 Hz), 7.89 (1H, t, J=2 Hz), 8.49 (1H, dd, J=2 Hz, 5 Hz), 8.56 (1H, dd, J=2 Hz, 8 Hz)
(3) 2-[3-(4-Acetylaminophenyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 2.21 (3H, s), 6.86 (1H, dd, J=5 Hz, 8 Hz), 7.3-7.5 (3H, m), 7.55-7.65 (5H, m), 7.84 (1H, s), 8.45-8.6 (2H, m)
(4) 2-[3-(4-Methoxycarbonylphenyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 3.96 (3H, s), 6.87 (1H, dd, J=5 Hz, 8 Hz), 7.4-7.55 (2H, m), 7.70 (3H, m), 7.92 (1H, t, J=2 Hz), 8.13 (2H, dt, J=8 Hz, 2 Hz), 8.5-8.6 (2H, m)
(5) 2-[3-(2-Fluorophenyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 6.86 (1H, dd, J=5 Hz, 8 Hz), 7.1-7.5 (6H, m), 7.70 (1H, d, J=8 Hz), 7.82 (1H, d, J=2 Hz), 7.5-7.6 (2H, m)
(6) 1-[3-[(3-Nitropyridin-2-yl)amino]phenyl]-1H-1,2,4-triazole
NMR (CDCl3, 300 MHz, xcex4): 6.93 (1H, dd, J=5 Hz, 8 Hz), 7.4-7.55 (2H, m), 7.61 (1H, dt, J=8 Hz, 2 Hz), 8.13 (1H, s), 8.30 (1H, t, J=2 Hz), 8.55-8.65 (3H, m)
(7) 3-Nitro-2-[3-(3-thienyl)phenylamino]pyridine
NMR (CDCl3, 300 MHz, xcex4): 6.86 (1H, dd, J=5 Hz, 8 Hz), 7.5-7.55 (5H, m), 7.61 (1H, m), 7.88 (1H, s), 8.5-8.6 (2H, m)
(8) 2-[3-(5-Chloro-2-thienyl)phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 6.85-6.95 (2H, m), 7.12 (1H, d, J=4 Hz), 7.32 (1H, dt, J=8 Hz, 2 Hz), 7.40 (1H, t, J=8 Hz), 7.58 (1H, m), 7.87 (1H, t, J=2 Hz), 8.5-8.6 (2H, m)
(9) 3-Nitro-2-[3-(2-thienyl)phenylamino]pyridine
NMR (CDCl3, 300 MHz, xcex4): 6.86 (1H, dd, J=5 Hz, 8 Hz), 7.10 (1H, dd, J=4 Hz, 5 Hz), 7.3-7.45 (4H, m), 7.60 (1H, m), 7.90 (1H, t, J=2 Hz), 8.5-8.6 (2H, m)
(10) 3-Nitro-2-[3-(4-pyridyl)phenylamino]pyridine
NMR (CDCl3, 300 MHz, xcex4): 6.89 (1H, dd, J=5 Hz, 8 Hz), 7.4-7.6 (4H, m), 7.72 (1H, dt, J=8 Hz, 2 Hz), 7.99 (1H, t, J=2 Hz), 8.5-8.6 (2H, m), 8.69 (2H, d, J=5 Hz)
(11) 3-Nitro-2-[3-(3-pyridyl)phenylamino]pyridine
NMR (CDCl3, 300 MHz, xcex4): 6.89 (1H, dd, J=5 Hz, 8 Hz), 7.35-7.45 (2H, m), 7.52 (1H, t, J=8 Hz), 7.68 (1H, dt, J=8 Hz, 2 Hz), 7.9-8.0 (2H, m), 8.5-8.6 (2H, m), 8.62 (1H, dd, J=2 Hz, 5 Hz), 8.90 (1H, d, J=2 Hz)
(12) 2-[3-(Benzoylamino)phenylamino]-3-nitropyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.01 (1H, dd, J=5 Hz, 8 Hz), 7.35 (1H, t, J=8 Hz), 7.44 (1H, d, J=8 Hz), 7.5-7.65 (4H, m), 7.98 (2H, d, J=8 Hz), 8.11 (1H, s), 8.5-8.6 (2H, m), 9.99 (1H, s), 10.31 (1H, s)
(13) 2-[3-(6-Methoxy-2-naphthyl)phenylamino]-3-nitropyridine
NMR (DMSO-d6, xcex4): 3.90 (3H, s), 7.01 (1H, m), 7.20 (1H, m), 7.37 (1H, m), 7.50 (1H, dd, J=8 Hz, 8 Hz), 7.57 (1H, m), 7.73 (1H, m), 7.84 (1H, m), 7.93 (2H, m), 8.04 (1H, m), 8.18 (1H, s), 8.56 (2H, m)
(14) 3-Nitro-2-(3-succinimidophenylamino)pyridine
NMR (CDCl3, 300 MHz, xcex4): 8.56-8.47 (2H, m), 7.79 (1H, s), 7.67 (1H, d, J=9 Hz), 7.48 (1H, t, J=9 Hz), 7.10 (1H, d, J=9 Hz), 6.91-6.84 (1H, m), 2.91 (4H, s)
(15) 2-[3-(5-Methoxycarbonylindol-1-yl)phenylamino]-3-nitropyridine
NMR (CDCl3, xcex4): 3.94 (3H, s), 6.78 (dH, d, J=3 Hz), 6.91 (1H, dd, J=8 Hz, 5 Hz), 7.28 (1H, m), 7.45 (1H, d, J=3 Hz), 7.52 (2H, m), 7.72 (1H, d, J=8 Hz), 7.95 (1H, d, J=8 Hz), 8.16 (1H, m), 8.45 (1H, s), 8.55 (2H, m)
(16) 2-[3-(3-Quinolyl)phenylamino]-3-nitropyridine
NMR (CDCl3, xcex4): 6.89 (1H, dd, J=8 Hz, 3 Hz), 7.55 (3H, m), 7.70 (2H, m), 7.92 (1H, d, J=8 Hz), 8.07 (1H, s), 8.14 (1H, d, J=8 Hz), 8.34 (1H, d, J=3 Hz), 8.52 (mH, m), 8.57 (1H, m), 9.21 (1H, d, J=3 Hz)
(17) 2-[3-(3-Cyclopentyloxy-4-methoxyphenyl)phenylamino]-3-nitropyridine
NMR (DMSO-d6, xcex4): 1.59 (2H, m), 1.74 (4H, m), 1.90 (2H, m), 3.79 (3H, s), 4.92 (1H, m), 7.00 (1H, dd, J=8 Hz, 5 Hz), 7.04 (1H, d, J=8 Hz), 7.20 (2H, m), 7.41 (2H, m), 7.63 (1H, m), 7.88 (1H, s), 8.53 (2H, m)
(18) 2-[3-(3-Methoxycarbonylphen yl)phenylamino]-3-nitropyridine
mp: 179-181xc2x0 C.
NMR (CDCl3, xcex4): 3.95 (3H, 5), 6.87 (1H, dd, J=8 Hz, 5 Hz), 7.50 (3H, m), 7.70 (1H, m), 7.82 (1H, m), 7.89 (1H, m), 8.04 (1H, m), 8.30 (1H, m), 8.52 (2H, m)
(19) 2-[3-[(E)-3-Methoxycarbonylvinylphenyl]phenylamino]-3-nitropyridine
NMR (DMSO-d6, xcex4): 3.74 (3H, s), 6.80 (1H, d, J=16 Hz), 7.03 (1H, dd, J=8 Hz, 5 Hz), 7.52 (3H, m), 7.76 (4H, m), 7.98 (1H, m), 8.07 (1H, m), 8.55 (2H, m)
(20) 2-[3-(4-Isoquinolyl)phenylamino]-3-nitropyridine
NMR (DSMO-d6, xcex4): 7.01 (1H, m), 7.33 (1H, dd, J=8 Hz, 2 Hz), 7.57 (1H, dd, J=8 Hz, 8 Hz), 7.7-7.9 (4H, m), 8.03 (1H, d, J=8 Hz), 8.23 (1H, d, J=8 Hz), 8.54 (3H, m), 9.36 (1H, s)
(21) 2-[3-(3-Acetamidophenyl) phenylamino]-3-nitropyridine
NMR (CDCl3, xcex4): 2.20 (3H, s), 6.83 (1H, dd, J=8 Hz, 5 Hz), 7.3-7.4 (4H, m), 7.45 (1H, dd, J=8 Hz, 8 Hz), 7.52 (1H, m), 7.67 (1H, m), 7.75 (1H, s), 7.83 (1H, m), 8.52 (2H, m)
(22) 3-[3-[(3-Nitropyridin-2-yl)amino]phenylcarbamoyl]-quinoline
NMR (DMSO-d6, 300 MHz, xcex4): 7.02 (1H, dd, J=5 Hz, 8 Hz), 7.35-7.5 (2H, m), 7.62 (1H, d, J=8 Hz), 7.74 (1H, t, J=8 Hz), 7.91 (1H, t, J=8 Hz), 8.1-8.2 (3H, m), 8.55-8.6 (2H, m), 8.99 (1H, s), 9.38 (1H, d, J=2 Hz)
(23) 2-[3-[(E)-2-(3,5-Dichlorophenyl)vinyl]phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 6.68 (1H, dd, J=5 Hz, 8 Hz) 6.99 (1H, d, J=16 Hz), 7.13 (1H, d, J=16 Hz), 7.27 (1H, m), 7.32 (1H, d, J=8 Hz), 7.35-7.45 (3H, m), 7.59 (1H, d, J=8 Hz), 7.83 (1H, s), 8.5-8.6 (2H, m)
(24) 2-[3-(3,5-Dichlorophenylcarbamoyl)phenylamino-3-nitropyridine
NMR (DMSO-d6, 300 MHz, xcex4): 7.04 (1H, dd, J=5 Hz, 8 Hz), 7.23 (1H, s), 7.55 (1H, t, J=8 Hz), 7.72 (1H, d, J=8 Hz), 7.9-8.0 (3H, m), 8.20 (1H, s), 8.5-8.6 (2H, m)
(25) 2-[3-[N-Methyl-N-(3,5-dichlorophenyl)carbamoyl]phenylamino]-3-nirtopyridine
NMR (CDCl3, 300 MHz, xcex4): 3.49 (3H, s), 6.88 (1H, dd, J=5 Hz, 8 Hz), 7.0-7.2 (4H, m), 7.28 (1H, t, J=8 Hz), 7.56 (1H, dd, J=2 Hz, 8 Hz), 7.94 (1H, s), 7.45-7.55 (2H, m)
(26) 2-(3-Carboxyphenylamino)-3-nitropyridine
NMR (DMSO-d6, xcex4): 7.03 (1H, dd, J=8 Hz, 5 Hz), 7.50 (1H, dd, J=8 Hz, 8 Hz), 7.71 (1H, m), 7.88 (1H, m), 8.25 (1H, m), 8.55 (2H, m)
(27) 6-Phenylthio-2-[3-(3-phenylureidophenyl]-3-nitropyridine
NMR (DMSO-d6, xcex4): 6.60 (1H, d, J=8 Hz), 7.00 (3H, m), 7.10 (1H, m), 7.29 (2H, m), 7.4-7.7 (8H, m), 8.38 (1H, d, J=8 Hz), 8.67 (2H, m)
A mixture of 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.20 g) and 10% palladium on carbon (0.25 g) in methanol (15 ml) and 1,4-dioxane (15 ml) was stirred under hydrogen (3 atm) at room temperature for 3 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-aminopyridine (1.10 g).
NMR (DMSO-d6, 300 MHz, xcex4): 2.05 (3H, s), 3.82 (3H, s), 5.12 (2H, s), 6.68 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, d, J=8 Hz), 7.52 (1H, d, J=5 Hz), 7.78 (1H, t, J=2 Hz), 7.90 (1H, m), 8.00 (1H, s), 8.21 (1H, s)
The following compounds were obtained according to a similar manner to that of Preparation 3, 31, 33, 52, 53, 54 or 71.
(1) 2-[3-(4-Acetylaminophenyl)phenylamino]-3-aminopyridine
NMR (DMSO-d6, 300 MHs, xcex4): 2.07 (3H, s), 5.09 (2H, s), 6.63 (1H, dd, J=5 Hz, 8 Hz), 6.91 (1H, dd, J=2 Hz, 8 Hz), 7.10 (1H, d, J=8 Hz), 7.29 (1H, t, J=8 Hz), 7.5-7.6 (3H, m), 7.65-7.7 (3H, m), 7.82 (2H, d, J=8 Hz)
(2) 3-Amino-2-[3-(2-pyridyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.12 (2H, s), 6.64 (1H, m), 6.92 (1H, d, J=8 Hz), 7.3-7.4 (2H, m), 7.53 (2H, d, J=8 Hz), 7.85-7.95 (4H, m), 8.27 (1H, s), 8.67 (1H, d, J=5 Hz)
(3) 3-Amino-2-[3-(3-pyridyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.09 (2H, s), 6.64 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, dd, J=2 Hz, 8 Hz), 7.18 (1H, dd, J=2 Hz, 8 Hz), 7.35 (1H, t, J=8 Hz), 7.45-7.55 (2H, m), 7.72 (1H, dd, J=2 Hz, 8 Hz), 7.85-7.95 (2H, m), 8.01 (1H, dt, J=8 Hz, 2 Hz), 8.57 (1H, dd, J=2 Hz, 5 Hz), 8.83 (1H, d, J=2 Hz)
(4) 3-Amino-2-[3-(4-pyridyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, dd, J=2 Hz, 8 Hz), 7.25 (1H, d, J=8 Hz), 7.38 (1H, t, J=8 Hz), 7.53 (1H, dd, J=2 Hz, 5 Hz), 7.64 (2H, d, J=5 Hz), 7.78 (1H, d, J=8 Hz), 7.91 (1H, s), 8.02 (1H, s), 8.63 (2H, d, J=5 Hz)
(5) 3-Amino-2-[3-(2-thienyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.66 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, dd, J=2 Hz, 8 Hz), 7.1-7.2 (2H, m), 7.27 (1H, t, J=8 Hz), 7.42 (1H, dd, J=2 Hz, 5 Hz), 7.5-7.55 (2H, m), 7.66 (1H, d, J=8 Hz), 7.86 (1H, s), 7.91 (1H, t, J=2 Hz)
(6) 3-Amino-2-[3-(5-chloro-2-thienyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.93 (1H, dd, J=2 Hz, 8 Hz), 7.1-7.2 (2H, m), 7.25-7.35 (2H, m), 7.54 (1H, dd, J=2 Hz, 5 Hz), 7.65 (1H, dd, J=2 Hz, 8 Hz), 7.89 (1H, d, J=2 Hz)
(7) 3-Amino-2-[3-(3-thienyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.08 (2H, s), 6.63 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, dd, J=2 Hz, 8 Hz), 7.18 (1H, d, J=8 Hz), 7.27 (1H, t, J=8 Hz), 7.47 (1H, dd, J=2 Hz, 5 Hz), 7.53 (1H, dd, J=2 Hz, 5 Hz), 7.63 (2H, m), 7.73 (1H, m), 7.79 (1H, s), 7.90 (1H, t, J=2 Hz)
(8) 1-[3-[(3-Aminopyridin-2-yl)amino]phenyl]-1H-1,2,4-triazole
NMR (DMSO-d6, 300 MHz, xcex4): 5.13 (2H, s), 6.69 (1H, dd, J=5 Hz, 8 Hz), 6.96 (1H, dd, J=2 Hz, 8 Hz), 7.30 (1H, m), 7.39 (1H, t, J=8 Hz), 7.55 (1H, dd, J=2 Hz, 5 Hz), 7.68 (1H, dt, J=8 Hz, 2 Hz), 8.07 (1H, s), 8.19 (1H, t, J=2 Hz), 8.22 (1H, s), 9.21 (1H, s)
(9) 3-Amino-2-[3-(2-fluorophenyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.64 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, dd, J=2 Hz, 8 Hz), 7.01 (1H, d, J=8 Hz), 7.25-7.55 (6H, m), 7.72 (1H, dt, J=8 Hz, 2 Hz), 7.80 (1H, d, J=2 Hz), 7.87 (1H, s)
(10) 3-Amino-2-[3-(4-methoxycarbonylphenyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 3.89 (3H, s), 5.10 (2H, s), 6.67 (1H, dd, J=5 Hz, 8 Hz), 6.94 (1H, dd, J=2 Hz, 8 Hz), 7.20 (1H, d, J=8 Hz), 7.37 (1H, t, J=8 Hz), 7.53 (1H, dd, J=2 Hz, 5 Hz), 7.79 (3H, m), 7.91 (1H, s), 7.98 (1H, t, J=2 Hz), 8.07 (2H, d, J=8 Hz)
(11) 3-Amino-2-[3-(morpholinocarbonyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 3.3-3.7 (8H, m), 5.09 (2H, s), 6.65 (.1H, dd, J=5 Hz, 8 Hz), 6.86 (1H, dt, J=8 Hz, 2 Hz), 6.92 (1H, dd, J=2 Hz, 8 Hz), 7.29 (1H, t, J=8 Hz), 7.51 (1H, dd, J=2 Hz, 5 Hz), 7.65 (1H, dt, J=8 Hz, 2 Hz), 7.73 (1H, t, J=2 Hz), 7.90 (1H, s)
(12) 3-Amino-2-[3,5-bis(methoxycarbonyl)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 3.88 (6H, s), 5.13 (2H, s), 6.71 (1H, dd, J=5 Hz, 8 Hz), 6.97 (1H, d, J=8 Hz), 7.55 (1H, d, J=5 Hz), 7.96 (1H, s), 8.29 (1H, s), 8.52 (1H, s)
(13) 3-Amino-2-[3-methoxycarbonyl-5-(2-naphthoylamino)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 3.89 (3H, s), 5.18 (2H, s), 6.70 (1H, dd, J=5, 8 Hz), 6.96 (1H, d, J=8 Hz), 7.57 (1H, m), 7.6-7.7 (2H, m), 7.95-8.15 (7H, m), 8.50 (1H, s), 8.63 (1H, s)
(14) 3-Amino-2-[3-(benzoylamino)phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.11 (2H, s), 6.64 (1H, m), 6.91 (1H, d, J=8 Hz), 7.15-7.3 (2H, m), 7.4-7.65 (5H, m), 7.79 (1H, s), 7.98 (2H, d, J=8 Hz), 8.08 (1H, s)
(15) 2-[3-(6-Methoxy-2-naphthyl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 3.45 (2H, br s), 3.93 (3H, s), 6.30 (1H, s), 6.80 (1H, dd, J=8 Hz, 5 Hz), 7.04 (1H, m), 7.16 (2H, m), 7.30 (2H, m), 7.39 (1H, m), 7.54 (1H, m), 7.71 (1H, m), 7.79 (2H, m), 7.87 (1H, m), 7.98 (1H, s)
(16) 2-[3-(5-Methoxycarbonylindol-1-yl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 3.48 (2H, s), 3.93 (3H, s), 6.42 (1H, s), 6.73 (1H, m), 6.81 (1H, m), 7.05 (2H, m), 7.21 (1H, m), 7.42 (1H, m), 7.61 (1H, m), 7.70 (1H, m), 7.88 (1H, m), 7.91 (1H, m), 8.42 (1H, m)
(17) 2-[3-(3-Quinolyl)phenylamino]-3-aminopyridine
NMR (DMSO-d6, xcex4): 5.12 (2H, s), 6.67 (1H, dd, J=8 Hz, 5 Hz), 6.95 (1H, d, J=8 Hz), 7.34 (1H, d, J=8 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.55 (1H, d, J=5 Hz), 7.67 (1H, dd, J=8 Hz, 8 Hz), 7.80 (2H, m), 7.95 (1H, s), 8.09 (2H, m), 8.59 (1H, m), 9.21 (1H, d, J=3 Hz)
(18) 2-[3-(3-Cyclopentyloxy-4-methoxyphenyl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 1.62 (2H, m), 1.85 (2H, m), 1.94 (4H, m), 3.45 (2H, m), 3.87 (3H, s), 4.85 (1H, m), 6.27 (1H, s), 6.79 (1H, dd, J=8 Hz, 5 Hz), 6.92 (1H, d, J=8 Hz), 7.03 (1H, d, J=8 Hz), 7.13 (3H, m), 7.23 (1H, m), 7.34 (1H, dd, J=8 Hz, 8 Hz), 7.42 (1H, m), 7.85 (1H, d, J=5 Hz)
(19) 2-[3-(3-Methoxycarbonylphenyl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 3.47 (2H, s), 3.94 (3H, s), 6.32 (1H, s), 6.79 (1H, dd, J=8 Hz, 5 Hz), 7.03 (1H, d, J=8 Hz), 7.22 (1H, m), 7.35 (2H, m), 7.49 (2H, m), 7.79 (1H, d, J=8 Hz), 7.85 (1H, m), 8.00 (1H, d, J=8 Hz), 8.28 (1H, s)
(20) 2-[3-[3-[(E)-2-Methoxycarbonylvinyl]phenyl]-phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 3.45 (2H, br s), 3.81 (3H, s), 6.30 (1H, s), 6.50 (1H, d, J=16 Hz), 6.81 (1H, m), 7.05 (1H, m), 7.17 (1H, m), 7.30 (1H, m), 7.36 (1H, m), 7.48 (2H, m), 7.60 (1H, m), 7.72 (1H, s), 7.75 (1H, d, J=16 Hz), 7.87 (1H, d, J=3 Hz)
(21) 2-[3-(4-Isoquinolyl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 3.50 (2H, br s), 6.40 (1H, s), 6.80 (1H, m), 7.03 (1H, m), 7.10 (1H, m), 7.44 (3H, m), 7.66 (2H, m), 7.85 (1H, m), 8.05 (2H, m), 8.52 (1H, s), 9.22 (1H, s)
(22) 2-[3-(3-Acetamidophenyl)phenylamino]-3-aminopyridine
NMR (CDCl3, xcex4): 2.13 (3H, s), 3.50 (2H, br s), 6.33 (1H, s), 6.77 (1H, dd, J=8 Hz, 5 Hz), 7.00 (1H, d, J=8 Hz), 7.12 (1H, dd, J=8 Hz, 2 Hz), 7.2-7.4 (5H, m), 7.50 (1H, m), 7.55 (1H, m), 7.61 (1H, s), 7.82 (1H, d, J=5 Hz)
(23) 2-(3-Iodophenylamino)-3-aminopyridine
NMR (DMSO-d6, xcex4): 5.06 (2H, s), 6.66 (1H, m), 6.92 (1H, m), 7.00 (1H, dd, J=8 Hz, 8 Hz), 7.15 (1H, m), 7.51 (1H, m), 7.61 (1H, m), 7.83 (1H, s), 8.08 (1H, s)
(24) 3-[3-[(3-Aminopyridin-2-yl)amino]phenylcarbamoyl]quinoline
NMR (DMSO-d6, 300 MHz, xcex4): 5.12 (2H, s), 6.65 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, d, J=8 Hz), 7.2-7.35 (2H, m), 7.45 (1H, d, J=8 Hz), 7.52 (1H, d, J=5 Hz), 7.73 (1H, t, J=8 Hz), 7.81 (1H, s), 7.90 (1H, t, J=8 Hz), 8.1-8.2 (3H, m), 8.97 (1H, d, J=2 Hz), 9.37 (1H, s)
(25) 3-Amino-2-[3-[(E)-2-(3,5-dichlorophenyl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.09 (2H, s), 6.64 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, d, J=8 Hz), 7.1-7.2 (2H, m), 7.28 (1H, t, J=8 Hz), 7.4-7.6 (4H, m), 7.72 (2H, s), 7.80 (1H, s), 7.84 (1H, s)
(26) 3-Amino-2-[3-[N-methyl-N-(3,5-dichlorophenyl)carbamoyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 3.37 (3H, s), 5.08 (2H, s), 6.63 (1H, dd, J=5 Hz, 8 Hz), 6.73 (1H, d, J=8 Hz), 6.90 (1H, d, J=8 Hz), 7.13 (1H, t, J=8 Hz), 7.3-7.45 (3H, m), 7.5-7.6 (2H, m), 7.83 (2H, m)
(27) 6-Phenylthio-2-[3-(3-phenylureido)phenylamino]-3-aminopyridine
NMR (DMSO-d6, xcex4): 4.50 (2H, br s), 6.5-7.6 (10H, m), 8.30 (1H, m), 8.95 (2H, m)
(28) 2-(3-Phenylsulfonylaminophenylamino)-3-aminopyridine
NMR (DMSO-d6, xcex4): 5.07 (2H, s), 6.55 (1H, m), 6.61 (1H, m), 6.89 (1H, m), 7.02 (1H, dd, J=8 Hz, 8 Hz), 7.25 (2H, m), 7.55 (5H, m), 7.82 (2H, m)
(29) 2-(3-Methoxycarbonylphenylamino)-3-aminopyridine
NMR (DMSO-d6, xcex4): 3.83 (3H, s), 5.30 (2H, br s), 6.68 (1H, dd, J=8 Hz, 6 Hz), 6.95 (1H, d, J=8 Hz), 7.37 (1H, dd, J=8 Hz, 8 Hz), 7.44 (1H, d, J=8 Hz), 7.51 (1H, d, J=6 Hz), 7.99 (1H, d, J=8 Hz), 8.09 (1H, s), 8.18 (1H, s)
To a mixture of 2-(3-amino-5-methoxycarbonylphenylamino)-3-nitropyridine (550 mg) and triethylamine (0.3 ml) in 1,4-dioxane (10 ml) was added 2-naphthoyl chloride (0.40 g). The mixture was stirred at room temperature for 15 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase containing orange solid was washed with water twice and the solid was collected to give 2-[3-methoxycarbonyl-5-(2-naphthoylamino)phenylamino]-3-nitropyridine (730 mg).
NMR (DMSO-d6, 300 MHz, xcex4): 3.90 (3H, s), 7.05 (1H, dd, J=5 Hz, 8 Hz), 7.6-7.7 (2H, m), 8.0-8.15 (5H, m), 8.29 (1H, t, J=2 Hz), 8.47 (1H, m), 8.55-8.6 (2H, m), 8.64 (1H, s)
To a mixture of 2-[3-amino-5-methoxycarbonylphenylamino]-3-nitropyridine (1.10 g), triethylamine (0.6 ml) and 4-dimethylaminopyridine (14 mg) in 1,4-dioxane (15 ml) was added acetic anhydride (0.40 ml). The mixture was stirred at room temperature for 20 hours, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.21 g).
NMR (CDCl3, 300 MHz, xcex4): 2.21 (3H, s), 3.93 (3H, s), 6.89 (1H, dd, J=5, 8 Hz), 7.49 (1H, s), 7.79 (1H, s), 8.01 (1H, s), 8.41 (1H, s), 8.5-8.6 (2H, m)
To a mixture of 3-nitroaniline (5.95 g) and triethylamine (6.0 ml) in dichloromethane (40 ml) was added dropwise a solution of benzoyl chloride (5.0 ml) in dichloromethane (20 ml). The mixture was stirred at room temperature for 15 minutes, then poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 1-benzoylamino-3-nitrobenzene (9.05 g).
NMR (CDCl3, 300 MHz, xcex4): 7.45-7.65 (4H, m), 7.90 (2H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.05-8.2 (2H, m), 8.50 (1H, s)
The solution of 3-nitro-2-(3-succinimidophenylamino)-pyridine (3.47 g) was hydrogenated with palladium on carbon (0.5 g) at 3 atm for 5 hours. The mixture was filtrated and evaporated to give 3-amino-2-(3-succinimidophenylamino)pyridine (2.89 g).
NMR (DMSO-d6, 300 MHz, xcex4): 8.00 (1H, s), 7.64 (1H, dd, J=8 Hz, 1 Hz), 7.56 (1H, d, J=1 Hz), 7.50 (1H, d, J=3 Hz), 7.31 (1H, t, J=8 Hz), 6.92 (1H, d, J=7 Hz), 6.70 (1H, d, J=7 Hz), 6.66 (1H, dd, J=8 Hz, 3 Hz), 5.23 (2H, br s), 2.69 (4H, s)
The following compound was synthesized from 3-nitroaniline and maleic anhydride according to a similar manner to that described in Organic Synthesis Collective Volume 5 pp944.
(Z)-3-(3-Nitrophenylcarbamoyl)acrylic acid
NMR (DMSO-d6, 300 MHz, xcex4): 6.34 (1H, d, J=10 Hz), 6.50 (1H, d, J=10 Hz), 7.63 (1H, t, J=8 Hz), 7.92 (1H, d, J=8 Hz), 7.95 (1H, d, J=8 Hz), 8.65 (1H, s)
MASS (FAB) (m/e): 235
The following compound was synthesized from (Z)-3-(3-nitrophenylcarbamoyl)acrylic acid according to a similar manner to that described in Organic Synthesis Collective Volume 5 pp944.
N-(3-Nitrophenyl)maleimide
NMR (DMSO-d6, 300 MHz, xcex4): 7.26 (2H, s), 7.77-7.88 (2H, m),8.22-8.31 (2H, m)
To a solution of N-(3-nitrophenyl)maleimide (26.3 g) in methanol-dioxane (1:1) was added suspension of palladium on carbon (2 g) in water. The reaction mixture was hydrogenated for 4 hours at 3 atm. (White crystal was precipitated.) The mixture was added 1N hydrochloric acid (ca. 300 ml) to dissolve the crude product. The mixture was filtrated and evaporated. Obtained residue was dissolved in water and basified by aqueous sodium hydrogencarbonate. Precipitate was collected by suction to give N-(3-aminophenyl)succinimide (12.6 g).
NMR (DMSO-d6, 300 MHz, xcex4): 2.72 (4H, s), 5.25 (2H, s), 6.33 (1H, d, J=7 Hz), 6.39 (1H, d, J=1 Hz), 6.58 (1H, dd, J=7 Hz, 1 Hz), 7.07 (1H, t, J=9 Hz)
MASS (FAB) (m/e): 191 (M+1)
A mixture of ethyl 4-hydroxy-3-methoxybenzoate (7.17 g), cyclopentyl bromide (4.7 ml) and potassium carbonate (7.6 g) in N,N-dimethylformamide (70 ml) was stirred at 80xc2x0 C. for 3 hours. Then the mixture was poured into water and extracted with ethyl acetate twice. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 4:1) to give ethyl 4-cyclopentyloxy-3-methoxybenzoate (8.58 g) as an oil.
NMR (CDCl3, 300 MHz, xcex4): 1.39 (3H, t, J=7 Hz), 1.55-2.10 (8H, m), 3.90 (3H, s), 4.36 (2H, q, J=7 Hz), 4.83 (1H, m), 6.88 (1H, d, J=8 Hz), 7.54 (1H, d, J=2 Hz), 7.65 (1H, dd, J=2 Hz, 8 Hz)
A mixture of ethyl 4-cyclopentyloxy-3-methoxybenzoate (1.06 g) and 4N aqueous sodium hydroxide (4 ml) in ethanol (8 ml) and 1,4-dioxane (8 ml) was stirred at 80xc2x0 C. for 3 hours. Then the mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 4-cyclopentyloxy-3-methoxybenzoic acid (730 mg).
NMR (CDCl3, 300 MHz, xcex4): 1.55-2.10 (8H, m), 3.90 (3H, s), 4.87 (1H, m), 6.91 (1H, d, J=8 Hz), 7.60 (1H, d, J=2 Hz), 7.74 (1H, dd, J=2 Hz, 8 Hz)
To a solution of 3-quinolinecarboxylic acid (2.50 g) in dichloromethane (50 ml) was added oxalyl chloride (2.6 ml) and three drops of N,N-dimethylformamide. After stirring at room temperature for 30 minutes, the mixture was concentrated and the residual solid was added to a mixture of 3-nitroaniline (1.60 g) and triethylamine (4.0 ml) in dichloromethane (40 ml). After stirring at room temperature for 15 minutes, the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate three times. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-(3-nitrophenylcarbamoyl)quinoline (2.98 g).
NMR (DMSO-d6, 300 MHz, xcex4): 7.7-7.8 (2H, m), 7.93 (1H, t, J=8 Hz), 8.02 (1H, dd, J=2 Hz, 8 Hz), 8.15-8.3 (3H, m), 8.84 (1H, m), 9.02 (1H, d, J=2 Hz), 9.40 (1H, s)
A mixture of 3-nitrostyrene (4.6 ml), 1,3-dichloro-5-iodobenzene (7.8 g), palladium(II) acetate (0.20 g), tetrabutylammonium chloride (8.4 g) and sodium bicarbonate (6.3 g) in N,N-dimethylformamide (40 ml) was stirred at 110xc2x0 C. for 4 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 1,3-dichloro-5-[(E)-2-(3-nitrophenyl)vinyl]benzene (7.93 g).
NMR (DMSO-d6, 300 MHz, xcex4): 7.4-7.55 (2H, m), 7.6-7.75 (4H, m), 8.05 (1H, d, J=8 Hz), 8.15 (1H, dd, J=2 Hz, 8 Hz), 8.43 (1H, t, J=2 Hz)
To a mixture of 3,5-dichloroaniline (8.1 g) and triethylamine (7.0 ml) in chloroform (100 ml) was added dropwise a solution of 3-nitrobenzoyl chloride (9.3 g) in chloroform (50 ml). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate. The resultant precipitate was collected and washed with chloroform and water to give 3-nitro-N-(3,5-dichlorophenyl)benzamide (12.50 g).
NMR (DMSO-d6, 300 MHz, xcex4): 7.38 (1H, s), 7.8-7.9 (3H, m), 8.39 (1H, d, J=8 Hz), 8.48 (1H, d, J=8 Hz), 8.80 (1H, s)
A mixture of 2-[3-(3,5-dichlorophenylcarbamoyl)phenylamino]-3-nitropyridine (565 mg) and iron powder (0.4 g) in acetic acid (5 ml) and 1,4-dioxane (5 ml) was stirred at 80xc2x0 C. for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-[3-(3,5-dichlorophenylcarbamoyl)phenylamino]pyridine (284 mg).
NMR (DMSO-d6, 300 MHz, xcex4): 5.12 (2H, s), 6.68 (1H, m), 6.93 (1H, d, J=8 Hz), 7.3-7.6 (4H, m), 7.9-8.1 (5H, m)
To a suspension of sodium hydride (60% in oil, 1.1 g) in N,N-dimethylformamide (20 ml) was added dropwise a solution of 3-nitro-N-(3,5-dichlorophenyl)benzamide (5.89 g) in N,N-dimethylformamide (40 ml). The mixture was stirred at room temperature for 1 hour, then iodomethane (3 ml) was added thereto. After stirring at room temperature for 1 hour, dilute hydrochloric acid was added to the mixture and extracted with ethyl acetate twice. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was solidified with isopropyl ether to give 3-nitro-N-methyl-N-(3,5-dichlorophenyl)benzamide (4.62 g).
NMR (CDCl3, 300 MHz, xcex4): 3.49 (3H, s), 7.00 (2H, s), 7.21 (1H, m), 7.48 (1H, t, J=8 Hz), 7.63 (1H, d, J=8 Hz), 8.15-8.25 (2H, m)
A mixture of 3-amino-2-(3-biphenylylamino)pyridine (157 mg) and 4-methyl-2-oxopentanoic acid (94 mg) in ethanol (3 ml) was stirred under reflux for 2 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 3:1) to give 4-(3-biphenylyl)-2-isobutyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (47 mg).
NMR (CDCl3, 300 MHz, xcex4): 1.07 (6H, d, J=7 Hz), 2.39 (1H, m), 2.90 (2H, d, J=7 Hz), 7.25-7.5 (6H, m), 7.6-7.8 (4H, m), 8.20 (1H, d, J=8 Hz), 8.43 (1H, d, J=5 Hz)
The following compounds were obtained according to a similar manner to that of Preparation 87.
(1) 4-(3-Iodophenyl)-2-methyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
NMR (DMSO-d6, xcex4): 2.48 (3H, s), 7.38 (3H, s), 7.78 (1H, s), 7.75 (1H, m), 8.20 (1H, m), 8.36 (1H, m)
(2) 2-Methyl-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
NMR (DMSO-d6, 300 MHz, xcex4): 2.79 (4H, s), 3.31 (3H, s), 7.30 (1H, s), 7.36-7.45 (3H, m), 7.65 (1H, t, J=8 Hz), 8.22 (1H, d, J=7 Hz), 8.37 (1H, d, J=5 Hz)
(3) 2-Isobutyl-4-[3-(2-naphthoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
NMR (CDCl3, 300 MHz, xcex4): 1.04 (6H, d, J=7 Hz), 2.38 (1H, m), 2.89 (2H, d, J=7 Hz), 6.85 (1H, dt, J=8 Hz, 2 Hz), 7.29 (1H, dd, J=5 Hz, 8 Hz), 7.45-7.60 (3H, m), 7.72 (1H, dd, J=2 Hz, 8 Hz), 7.8-7.9 (5H, m), 8.18 (1H, dd, J=2 Hz, 8 Hz), 8.32 (1H, s), 8.40 (1H, dd, J=2 Hz, 5 Hz), 8.52 (1H, s)
(4) 2-Methyl-4-(3-methoxycarbonylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
NMR (DMSO-d6, 300 MHz, xcex4): 2.49 (3H, s), 3.86 (3H, s), 7.39 (1H, dd, J=4 Hz, 7 Hz), 7.67 (1H, d, J=7 Hz), 7.72 (1H, dd, J=6 Hz, 7 Hz), 7.97 (1H, s), 8.08 (1H, d, J=7 Hz), 8.22 (1H, d, J=6 Hz), 8.35 (1H, d, J=4 Hz)
(5) 4-(3-Biphenylyl)-2-(1-methylpropyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
NMR (CDCl3, 300 MHz, xcex4): 1.00 (3H, t, J=7 Hz), 1.34 (3H, d, J=7 Hz), 1.65 (1H, m), 1.98 (1H, m), 3.50 (1H, m), 7.25-7.45 (5H, m), 7.52 (1H, s), 7.6-7.7 (3H, m), 7.76 (1H, dd, J=2 Hz, 8 Hz), 8.20 (1H, dd, J=2 Hz, 8 Hz), 8.42 (1H, d, J=5 Hz)
(6) 2-Isobutyl-4-[3-(1H-1,2,4-triazol-1-yl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
NMR (CDCl3, 300 MHz, xcex4): 1.07 (6H, d, J=7 Hz), 2.38 (1H, m), 2.90 (2H, d, J=7 Hz), 7.3-7.4 (2H, m), 7.7-7.8 (2H, m), 7.86 (1H, dd, J=2 Hz, 8 Hz), 8.10 (1H, s), 8.40 (1H, dd, J=2 Hz, 5 Hz), 8.60 (1H, s)
(7) 2-Methyl-4-[3-(1-naphthyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
mp: 196-198xc2x0 C.
NMR (CDCl3, xcex4): 2.68 (3H, s), 7.30 (1H, dd, J=8 Hz, 6 Hz), 7.38 (1H, m), 7.4-7.55 (5H, m), 7.70 (2H, m), 7.88 (2H, m), 8.09 (1H, m), 8.15 (1H, d, J=8 Hz), 8.47 (1H, d, J=6 Hz)
(8) 2-Methyl-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
NMR (CDCl3, 300 MHz, xcex4): 2.68 (3H, s), 7.25-7.50 (6H, m), 7.59-7.68 (3H, m), 7.50 (1H, dd, J=8 Hz, 3 Hz), 8.16 (1H, dd, J=8 Hz, 3 Hz), 8.41 (1H, dd, J=7 Hz, 3 Hz)
(9) 2-Methyl-4-(3-acetamidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
NMR (DMSO-d6, 300 MHz, xcex4): 2.04 (3H, s), 2.49 (3H, s), 6.98 (1H, d, J=7 Hz), 7.39 (1H, dd, J=5 Hz, 7 Hz), 7.44 (1H, dd, J=7 Hz, 7 Hz), 7.57 (1H, d, J=7 Hz), 7.65 (1H, s), 8.21 (1H, d, J=7 Hz), 8.47 (1H, d, J=5 Hz)
A mixture of 3-amino-2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]pyridine (180 mg) and 2-oxosuccinic acid (90 mg) in ethanol (4 ml) was stirred under reflux for 1.5 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with ethanol to give 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-methyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (100 mg).
NMR (CDCl3, 300 MHz, xcex4): 1.5-1.65 (2H, m), 1.75-2.0 (6H, m), 2.67 (3H, s), 3.91 (3H, s), 4.73 (1H, m), 6.77 (1H, d, J=2 Hz), 6.82 (1H, dd, J=2 Hz, 8 Hz), 7.04 (1H, d, J=8 Hz), 7.29 (1H, m), 8.15 (1H, d, J=8 Hz), 8.46 (1H, d, J=5 Hz)
The suspension of 2-methyl-4-(3-acetamidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (8.6 g) in 3N hydrochloric acid (50 ml) was refluxed for an hour. The mixture was made basic by sodium bicarbonate (15 g) to obtain 2-methyl-4-(3-aminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (7.4 g) in yellow powder.
NMR (CDCl3, 300 MHz, xcex4): 2.64 (3H, s), 3.80 (2H, br s), 6.57 (1H, d, J=3 Hz), 6.63 (1H, d, J=7 Hz), 6.81 (1H, dd, J=7 Hz, 3 Hz), 7.25-7.30 (2H, m), 7.35 (1H, dd, J=7 Hz, 7 Hz), 8.13 (1H, d, J=7 Hz), 8.44 (1H, m)
The following compound was obtained according to a similar manner to that of Preparation 73 or 74.
2-(3-Phenylsulfonylaminophenylamino)-3-nitropyridine
NMR (DMSO-d6, xcex4): 6.83 (1H, m), 7.00 (1H, dd, J=8 Hz, 4 Hz), 7.20 (2H, m), 7.58 (4H, m), 7.82 (2H, m), 8.50 (2H, m), 9.87 (1H, s)
A mixture of 2-methoxy-5-nitrophenol (4.86 g), cyclopentyl bromide (3.4 ml) and potassium carbonate (4.8 g) in N,N-dimethylformamide (50 ml) was stirred at 50xc2x0 C. for 3 hours. Then the mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-cyclopentyloxy-4-methoxy-1-nitrobenzene (5.05 g).
NMR (CDCl3, 300 MHz, xcex4): 1.6-2.1 (8H, m), 3.94 (3H, s), 4.86 (1H, m), 6.90 (1H, d, J=8 Hz), 7.75 (1H, d, J=2 Hz), 7.90 (1H, dd, J=2 Hz, 8 Hz)
A mixture of 3-cyclopentyloxy-4-methoxy-1-nitrobenzene (5.02 g), iron powder (4.8 g) and hydrochloric acid (35%, 15 ml) in ethanol (40 ml) was stirred under reflux for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give 3-cyclopentyloxy-4-methoxyaniline (2.60 g) as an oil.
NMR (DMSO-d6, 300 MHz, xcex4): 1.5-1.9 (8H, m), 3.59 (3H, s), 4.55-4.7 (3H, m), 6.05 (1H, m), 6.23 (1H, d, J=2 Hz), 6.61 (1H, d, J=8 Hz)
A mixture of 2-chloro-3-nitropyridine (2.17 g), 3-cyclopentyloxy-4-methoxyaniline (2.58 g) and potassium carbonate (2.6 g) in 1,4-dioxane (30 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]-3-nitropyridine (1.35 g) as an orange solid.
NMR (CDCl3, 300 MHz, xcex4): 1.55-1.7 (2H, m), 1.8-2.0 (6H m), 3.86 (3H, s), 4.79 (1H, m), 6.79 (1H, dd, J=5 Hz, 8 Hz), 6.89 (1H, d, J=8 Hz), 7.09 (1H, m), 7.19 (1H, m), 8.46 (1H, d, J=5 Hz), 8.52 (1H, dd, J=2 Hz, 8 Hz)
A mixture of 2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]-3-nitropyridine (1.30 g) and 10% palladium on carbon (0.3 g) in ethanol (20 ml) and 1,4-dioxane (20 ml) was stirred under hydrogen (3 atm) at room temperature for 1 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 3-amino-2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]pyridine (992 mg).
NMR (DMSO-d6, 300 MHz, xcex4): 1.5-1.95 (8H, m), 3.69 (3H, s), 4.70 (1H, m), 6.58 (1H, dd, J=5 Hz, 8 Hz), 6.8-6.9 (2H, m), 7.15 (1H, m), 7.31 (1H, d, J=2 Hz), 7.42 (1H, d, J=5 Hz), 7.70 (1H, s)
To a mixture of 3-nitroaniline (2.07 g) and triethylamine (2.3 ml) in 1,4-dioxane (40 ml) was added 2-naphthoyl chloride (3.00 g) and the mixture was stirred at room temperature for 30 minutes. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate three times. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-(3-nitrophenyl)-2-naphthalenecarboxamide (3.02 g).
NMR (DMSO-d6, 300 MHz, xcex4): 7.6-7.75 (3H, m), 7.95-8.15 (5H, m), 8.28 (1H, dt, J=8 Hz, 2 Hz), 8.65 (1H, s), 8.87 (1H, t, J=2 Hz)
A mixture of N-(3-nitrophenyl)-2-naphthalenecarboxamide (2.94 g), iron powder (3.0 g) and hydrochloric acid (35%, 9 ml) in ethanol (30 ml) was stirred at 80xc2x0 C. for 2 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-(3-aminophenyl)-2-naphthalenecarboxamide (2.17 g).
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.34 (1H, dt, J=8 Hz, 2 Hz), 6.91 (1H, dt, J=8 Hz, 2 Hz), 6.99 (1H, t, J=8 Hz), 7.17 (1H, t, J=2 Hz), 7.6-7.7 (2H, m), 7.95-8.1 (4H, m), 8.55 (1H, s)
A mixture of 2-chloro-3-nitropyridine (0.87 g), N-(3-aminophenyl)-2-naphthalenecarboxamide (1.31 g) and potassium carbonate (1.0 g) in 1,4-dioxane (20 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[3-(2-naphthoylamino)phenylamino]-3-nitropyridine (961 mg) as an orange solid.
NMR (DMSO-d6, 300 MHz, xcex4): 7.02 (1H, dd, J=5 Hz, 8 Hz), 7.39 (1H, t, J=8 Hz), 7.47 (1H, d, J=8 Hz), 7.6-7.7 (3H, m), 8.0-8.2 (5H, m), 8.55-8.65 (3H, m)
A mixture of 2-[3-(2-naphthoylamino)phenylamino]-3-nitropyridine (948 mg), iron powder (0.55 g) and hydrochloric acid (35%, 2 ml) in ethanol (8 ml) was stirred at 80xc2x0 C. for 30 minutes. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-[3-(2-naphthoylamino)phenylamino]pyridine (682 mg).
NMR (DMSO-d6, 300 MHz, xcex4): 5.11 (2H, s), 6.64 (1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, dd, J=2 Hz, 8 Hz), 7.2-7.3 (2H, m), 7.45 (1H, dt, J=8 Hz, 2 Hz), 7.52 (1H, dd, J=2 Hz, 5 Hz), 7.6-7.7 (2H, m), 7.80 (1H, s), 8.0-8.15 (5H, m), 8.60 (1H, s)
The following compound was obtained by subjecting 2-(3-carboxyphenylamino)-3-aminopyridine to methyl esterification in the conventional manner.
2-(3-Methoxycarbonylphenylamino)-3-aminopyridine
NMR (CDC3, xcex4): 3.95 (3H, s), 6.89 (1H, dd, J=8 Hz, 5 Hz), 7.49 (1H, dd, J=8 Hz, 8 Hz), 7.86 (1H, m), 7.92 (1H, m), 8.30 (1H, m), 8.53 (1H, m)
A mixture of 3-nitrostyrene (3.98 g), 3,5-dichloropyridine (3.70 g), palladium(II) acetate (0.20 g), tetrabutylammonium chloride (7.0 g) and sodium bicarbonate (5.3 g) in N,N-dimethylformamide (35 ml) was stirred at 135xc2x0 C. for 2 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-chloro-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (3.01 g).
NMR (CDCl3, 300 MHz, xcex4): 7.1-7.3 (2H, m), 7.59 (1H, t, J=8 Hz), 7.8-7.9 (2H, m), 8.18 (1H, m), 8.40 (1H, t, J=2 Hz), 8.51 (1H, d, J=2 Hz), 8.63 (1H, s)
A mixture of 3-chloro-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (2.99 g), iron powder (2.6 g) and hydrochloric acid (35%, 8 ml) in methanol (50 ml) was stirred at 60xc2x0 C. for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-[(E)-2-(3-aminophenyl)vinyl]-5-chloropyridine (1.33 g).
NMR (DMSO-d6, 300 MHz, xcex4): 5.13 (2H, s), 6.54 (1H, d, J=8 Hz), 6.79 (2H, m), 7.0-7.15 (2H, m), 7.37 (1H, d, J=16 Hz), 8.21 (1H, s), 8.47 (1H, d, J=2 Hz), 8.70 (1H, s)
The following compound was obtained according to a similar manner to that of Preparation 1, 5, 27, 28, 47, 48, 49, 68 or 69.
2-[3-(E)-2-(-Chloropyridin-3-yl)vinyl]phenylamino]-3-nitropyridine
NMR (CDCl3, 300 MHz, xcex4): 6.88 (1H, dd, J=5 Hz, 8 Hz), 7.06 (1H, d, J=16 Hz), 7.20 (1H, d, J=16 Hz), 7.3-7.45 (2H, m), 7.61 (1H, d, J=8 Hz), 7.85 (2H, m), 8.47 (1H, s), 8.5-8.6 (3H, m)
The following compound was obtained according to a similar manner to that of Preparation 3, 31, 33, 52, 53, 54 or 71.
3-Amino-2-[3-[(E)-2-(5-chloropyridin-3-yl)vinyl]phenylamino]pyridine
NMR (DMSO-d6, 300 MHz, xcex4): 5.10 (2H, s), 6.64 (1H, dd, J=5 Hz, 8 Hz), 6.91 (1H, d, J=8 Hz), 7.1-7.3 (3H, m), 7.4-7.65 (3H, m), 7.75-7.9 (2H, m), 8.27 (1H, s), 8.48 (1H, s), 8.73 (1H, s)